ObjectiveTo analyze the pharmacodynamic substance basis of Shangkeling Spray and its potential mechanisms in intervening knee osteoarthritis （KOA） using ultra-performance liquid chromatography-tandem mass spectrometry （UPLC-MS）， network pharmacology， and molecular docking technology. MethodsUPLC-MS was used to identify the chemical components of Shangkeling Spray. Pharmacokinetic properties were employed to screen potential active ingredients. Network pharmacology methods were utilized to collect potential targets of these ingredients and the pathological gene set of KOA. An "active ingredient-disease" target network was constructed using databases such as STRING. Gene Ontology （GO） and Kyoto Encyclopedia of Genes and Genomes （KEGG） functional enrichment analyses were performed using clusterProfiler. Libraries including NumPy were employed to calculate shortest path lengths to identify dominant pharmacodynamic links. Core gene clusters were identified using MCODE， validated through the Gene Expression Omnibus （GEO） database， and molecular docking was performed between key active ingredients and core targets. ResultsA total of 322 and 314 chemical components were identified under positive and negative ion modes， respectively， with 410 components in total after de-duplication， mainly including flavonoids， coumarins， terpenoids， organic acids， and alkaloids. Analysis of the "active ingredient-disease" network identified "development and regeneration"， "cell growth and death"， "immune system"， and "nervous system" as the dominant pharmacodynamic links of Shangkeling Spray in the treatment of KOA. Molecular docking showed that key active ingredients， such as bletillin A， formononetin， morin， oxymatrine， aconitine， gallic acid， curdione， apigenin， naringenin， and oleanolic acid， tightly bound to functional domains of 10 key targets including Jun proteins（JUN）， interleukin-6 （IL-6）， protein kinase B1 （Akt1）， Caspase-3， nuclear transcription factor-κB subunit p65（RELA）， nuclear factor-kappaB1（NF-κB1）， Cyclin D₁， mammalian target of rapamycin（mTOR）， tumor necrosis factor （TNF）， and Fos proto-oncogene protein （FOS）. These interactions synergistically regulated the phosphatidylinositol 3-kinase （PI3K）/Akt/mTOR-related signaling axis and nervous system-related pathways， mediating cartilage repair， reducing inflammation and pain， and improving KOA. ConclusionThis study preliminarily clarifies the pharmacodynamic substance basis of Shangkeling Spray and suggests that its main active ingredients may improve KOA by synergistically regulating the PI3K/Akt/mTOR-related pathways， providing a reference for subsequent exploration of its substance benchmark and mechanism of action.

ObjectiveThis paper aims to observe the syndrome improvement and negative antigen conversion rate of Qingxuan Daozhi formula in the treatment of influenza in children （heat accumulation in the lung and stomach syndrome）. MethodsThrough a multi-center randomized controlled methodology design，confirmed influenza cases were collected from October 2022 to April 2023 in the pediatrics department of eight hospitals，such as Dongfang Hospital of Beijing University of Chinese Medicine. A total of 180 children with influenza and heat accumulation in the lung and stomach syndrome conforming to the standard were recruited through the clinic. The sick children meeting the inclusion criteria were randomly divided into groups by a block-randomized method. The children in the experimental group were treated with Qingxuan Daozhi formula for five days，and those in the control group were treated with Oseltamivir Phosphate Granules for five days. The primary efficacy indicator was the negative conversion rate of influenza antigen detection. Secondary efficacy indicators were the Canadian acute respiratory illness and flu scale （CARIFS） and the incidence of complications，severe cases， and critical cases. Follow-up observation was conducted on the day of enrollment，48 hours after medication，72 hours after medication， and （6+1） d after medication. ResultsOne hundred and eighty participants were randomly assigned to the experimental group （90 cases） or the control group （90 cases）. All participants were followed up during the study. Comparison of influenza antigen detection results in the primary efficacy indicators showed that the average time of negative influenza antigen conversion in the experimental group was （5.29±1.25） d，and that in the control group was （5.40±1.68） d，without a statistically significant difference. After five days of intervention，52 cases in the experimental group and 51 cases in the control group converted to negative，without a statistically significant difference. CARIFS score results in the secondary efficacy indicators showed that during 72 hours after intervention，there were statistically significant differences between the experimental group and the control group in three dimensions， including headache，muscle soreness， and the need for extra care （P<0.05）. On the （6+1） days after the intervention，the differences in both the experimental group and the control group were statistically significant in 10 dimensions， including sore throat，bad sleep，uncomfortable feeling，poor spirit and fatigue，crying more than usual，the need for extra care，symptom，function，influence on parents，and total score （P<0.05）. The comparison results within the group in the dimensional scores of symptom， function， and influence on parents，as well as the CARIFS total score showed that with the delay of follow-up time，scores of both groups decreased significantly，with a statistically significant difference （P<0.01）. Inter-group comparison results showed that the mean score of the experimental group was higher than that of the control group at the time of enrollment. With the progress of intervention，the score of the experimental group was significantly decreased compared with that of the control group. At the end of follow-up，the mean score of the experimental group was lower than that of the control group，with no statistically significant difference. In terms of the incidence of complications，severe cases， and critical cases， there were no complications，severe cases， and critical cases in the two groups，without a statistically significant difference. ConclusionThe symptom improvement effect and negative antigen conversion rate of Qingxuan Daozhi formula in the treatment of influenza in children （heat accumulation in the lung and stomach syndrome） are not inferior to Oseltamivir Phosphate granules， and children's acceptance is better. It can be more widely used in clinical treatment of influenza in children （heat accumulation in the lung and stomach syndrome）.

BACKGROUND: The association of systemic inflammatory response index (SIRI) with prognosis of coronary artery disease (CAD) patients has never been investigated in a large sample with long-term follow-up. This study aimed to explore the association of SIRI with all-cause and cause-specific mortality in a nationally representative sample of CAD patients from United States. METHODS: A total of 3386 participants with CAD from the National Health and Nutrition Examination Survey (NHANES) 1999-2018 were included in this study. Cox proportional hazards model, restricted cubic spline (RCS), and receiver operating characteristic curve (ROC) were performed to investigate the association of SIRI with all-cause and cause-specific mortality. Piece-wise linear regression and sensitivity analyses were also performed. RESULTS: During a median follow-up of 7.7 years, 1454 all-cause mortality occurred. After adjusting for confounding factors, higher lnSIRI was significantly associated with higher risk of all-cause (HR = 1.16, 95% CI: 1.09-1.23) and CVD mortality (HR = 1.17, 95% CI: 1.05-1.30) but not cancer mortality (HR = 1.17, 95% CI: 0.99-1.38). The associations of SIRI with all-cause and CVD mortality were detected as J-shaped with threshold values of 1.05935 and 1.122946 for SIRI, respectively. ROC curves showed that lnSIRI had robust predictive effect both in short and long terms. CONCLUSIONS SIRI was independently associated with all-cause and CVD mortality, and the dose-response relationship was J-shaped. SIRI might serve as a valid predictor for all-cause and CVD mortality both in the short and long terms.

OBJECTIVES: Anxiety is a common negative emotion. Under current social circumstances, university young teachers face multiple stressors and are more prone to anxiety, seriously threatening their physical and mental health. This study aims to investigate the impact of job insecurity on anxiety of university young teachers, while exploring the mediating roles of perceived stress and insomnia on this relationship. METHODS: Using convenience sampling, young teachers from a general university in a Chinese province were surveyed online. Scores of the Job Insecurity Scale, Perceived Stress Scale, Athens Insomnia Scale-Short Form, and Generalized Anxiety Disorder Scale were collected. A chain mediation analysis was conducted using the PROCESS macro. RESULTS: A total of 798 subjects were finally included. The detection rate of anxiety among university young teachers was 36.47%. Mediation analysis showed that job insecurity not only had a direct effect on anxiety, but also indirectly affected anxiety via perceived stress (46.42% of the total effect) and insomnia (7.45%), as well as through the chain-mediating path of perceived stress→ insomnia (13.18%; all P<0.05). CONCLUSIONS Job insecurity is a significant predictor of anxiety in young university faculty. Perceived stress and insomnia serve as sequential mediators in this relationship. Targeted interventions addressing job insecurity, stress perception, and sleep disturbances, alongside efforts to improve mental health literacy and the working environment, may help promote the overall well-being of university young teachers.
Humans ; Sleep Initiation and Maintenance Disorders/epidemiology* ; Universities ; Female ; Anxiety/psychology* ; Male ; Stress, Psychological/psychology* ; Adult ; Faculty/psychology* ; Surveys and Questionnaires ; China/epidemiology* ; Occupational Stress ; Job Security

Targeting T-cell is a strategy to control allogeneic response disorders, such as acute graft-versus-host disease (GVHD) which is an important cause of therapy-failure after allogeneic hematopoietic cell transplants. Free fatty acid receptor-4 (FFAR4) is a regulator of obesity but its role in T-cell and allogeneic reactions is unknown. Here, we found knockout of Ffar4 in donor T-cells in a mouse allograft model increased acute GVHD whereas the natural FFAR4 ligands and the synthetic FFAR4 agonists decreased it. FFAR4 agonist-mediated anti-acute GVHD effects depended on FFAR4-expression in donor T-cells. The FFAR4 agonist CpdA suppressed donor T-cell-mediated alloreaction by activating an aryl hydrocarbon receptor (AhR) pathway. CpdA recruited β-Arrestin2 to FFAR4 which facilitated nuclear translocation of AhR and upregulation of IL-22. The CpdA-mediated anti-acute GVHD effect was absent in mice receiving Ahr-knockout or Il22-knockout T-cells. Recipient-expressing Ffar4 was also important for the anti-acute GVHD effect of CpdA which inhibited activation of antigen presenting cells. Importantly, CpdA decreased acute GVHD in obese mice, an effect also depended on Ffar4-expression in donor T-cells and recipients. Our study shows the immunoregulatory effect of FFAR4 in T-cell, and targeting FFAR4 might be a relative option for controlling allogeneic reactions in obese patients.

Approximately 30%-40% of epilepsy patients do not respond well to adequate anti-seizure medications (ASMs), a condition known as pharmacoresistant epilepsy. The management of pharmacoresistant epilepsy remains an intractable issue in the clinic. Its early prediction is important for prevention and diagnosis. However, it still lacks effective predictors and approaches. Here, a classical model of pharmacoresistant temporal lobe epilepsy (TLE) was established to screen pharmacoresistant and pharmaco-responsive individuals by applying phenytoin to amygdaloid-kindled rats. Ictal electroencephalograms (EEGs) recorded before phenytoin treatment were analyzed. Based on ictal EEGs from pharmacoresistant and pharmaco-responsive rats, a convolutional neural network predictive model was constructed to predict pharmacoresistance, and achieved 78% prediction accuracy. We further found the ictal EEGs from pharmacoresistant rats have a lower gamma-band power, which was verified in seizure EEGs from pharmacoresistant TLE patients. Prospectively, therapies targeting the subiculum in those predicted as "pharmacoresistant" individual rats significantly reduced the subsequent occurrence of pharmacoresistance. These results demonstrate a new methodology to predict whether TLE individuals become resistant to ASMs in a classic pharmacoresistant TLE model. This may be of translational importance for the precise management of pharmacoresistant TLE.
Epilepsy, Temporal Lobe/diagnosis* ; Animals ; Drug Resistant Epilepsy/drug therapy* ; Electroencephalography/methods* ; Rats ; Anticonvulsants/pharmacology* ; Neural Networks, Computer ; Male ; Humans ; Phenytoin/pharmacology* ; Adult ; Disease Models, Animal ; Female ; Rats, Sprague-Dawley ; Young Adult ; Convolutional Neural Networks

OBJECTIVE: This study aims to elucidate the therapeutic potential of osthole for the treatment of atopic dermatitis (AD), focusing on its ability to alleviate chronic pruritus (CP) and the underlying molecular mechanisms. METHODS: In this study, we investigated the anti-inflammatory effects of osthole in both a 2,4-dichloronitrobenzene (DNCB)-induced AD mouse model and tumor necrosis factor-α (TNF-α) and interferon-γ (IFN-γ) stimulated huma immortalized epidermal (HaCaT) cells. The anti-itch effect of osthole was specifically assessed in the AD mouse model. Using methods such as hematoxylin and eosin (HE) staining, enzyme-linked immunosorbent assay (ELISA), western blot (WB), quantitative real-time PCR (qRT-PCR), and immunofluorescence staining. RESULTS: Osthole improved skin damage and clinical dermatitis scores, reduced scratching bouts, and decreased epidermal thickness AD-like mice. It also reduced the levels of interleukin (IL)-31 and IL-31 receptor A (IL-31 RA) in both skin tissues and HaCaT cells. Furthermore, Osthole suppressed the protein expression levels of phosphor-p65 (p-p65) and phosphor-inhibitor of nuclear factor kappa-Bα (p-IκBα). Meanwhile, it increased the protein expression levels of peroxisome proliferator-activated receptor α (PPARα) and PPARγ in HaCaT cells. CONCLUSION These findings indicated that osthole effectively inhibited CP in AD by activating PPARα, PPARγ, repressing the NF-κB signaling pathway, as well as the expression of IL-31 and IL-31 RA.

Diabetic foot (DF) is one of the most serious chronic complications of diabetes. The incidence rate among global diabetes patients is as high as 15% to 25%, and about 50% of patients will develop contralateral foot ulcers within 5 years after the first unilateral ulcer. As a non-invasive prevention and control solution, the application progress of functional insoles is mainly reflected in the following aspects:(1) Material innovation. The application of new composite materials and smart materials has significantly enhanced the pressure reduction effect and comfort. (2) Structural optimization. The development of multi-layer design and local pressure reduction structure has achieved more precise pressure distribution regulation. (3) Manufacturing process. 3D printing and parametric design have enabled the personalized customization of functional insoles. (4) Intelligent monitoring. It integrates functions such as pressure sensing and temperature monitoring, achieving real-time monitoring and early warning of foot conditions. Clinical research has confirmed that personalized functional insoles could reduce the incidence of foot ulcers and shorten the healing time of ulcers. At present, the research hotspots mainly focus on the development of smart materials, the construction of multi-functional integration and remote monitoring systems. However, in-depth research is still needed in the aspects of biomechanical mechanisms, standardized evaluation systems and long-term efficacy assessment. The development of future functional insoles should focus on the coordinated advancement of "personalization-intelligence-standardization", with the aim of providing more effective solutions for the prevention and treatment of DF.
Humans ; Diabetic Foot/therapy* ; Foot Orthoses

Gastric cancer (GC) is characterized by high morbidity and mortality rates. Chinese agarwood comprises the resin-containing wood of Aquilaria sinensis (Lour.) Gilg., traditionally utilized for treating asthma, cardiac ischemia, and tumors. However, comprehensive research regarding its anti-GC effects and underlying mechanisms remains limited. In this study, Chinese agarwood petroleum ether extract (CAPEE) demonstrated potent cytotoxicity against human GC cells, with half maximal inhibitory concentration (IC₅₀) values for AGS, HGC27, and MGC803 cells of 2.89, 2.46, and 2.37 μg·mL^-1, respectively, at 48 h. CAPEE significantly induced apoptosis in these GC cells, with B-cell lymphoma-2 (BCL-2) associated X protein (BAX)/BCL-2 antagonist killer 1 (BAK) likely mediating CAPEE-induced apoptosis. Furthermore, CAPEE induced G₀/G₁ phase cell cycle arrest in human GC cells via activation of the deoxyribonucleic acid (DNA) damage-p21-cyclin D1/cyclin-dependent kinase 4 (CDK4) signaling axis, and increased Fe²⁺, lipid peroxides and reactive oxygen species (ROS) levels, thereby inducing ferroptosis. Ribonucleic acid (RNA) sequencing, real-time quantitative polymerase chain reaction (RT-qPCR), and Western blotting analyses revealed CAPEE-mediated upregulation of heme oxygenase-1 (HO-1) in human GC cells. RNA interference studies demonstrated that HO-1 knockdown reduced CAPEE sensitivity and inhibited CAPEE-induced ferroptosis in human GC cells. Additionally, CAPEE administration exhibited robust in vivo anti-GC activity without significant toxicity in nude mice while inhibiting tumor cell growth and promoting apoptosis in tumor tissues. These findings indicate that CAPEE suppresses human GC cell growth through upregulation of the DNA damage-p21-cyclin D1/CDK4 signaling axis and HO-1-mediated ferroptosis, suggesting its potential as a candidate drug for GC treatment.
Animals ; Humans ; Mice ; Antineoplastic Agents, Phytogenic ; Apoptosis/drug effects* ; Cell Line, Tumor ; Cyclin D1/genetics* ; Cyclin-Dependent Kinase 4/genetics* ; DNA Damage/drug effects* ; Drugs, Chinese Herbal/pharmacology* ; Ferroptosis/drug effects* ; G1 Phase Cell Cycle Checkpoints/drug effects* ; Heme Oxygenase-1/genetics* ; Mice, Inbred BALB C ; Mice, Nude ; Plant Extracts/pharmacology* ; Stomach Neoplasms/physiopathology* ; Thymelaeaceae/chemistry* ; Up-Regulation/drug effects*

OBJECTIVE: Observational studies have found associations between inflammatory bowel disease (IBD) and the risk of dementia, including Alzheimer's dementia (AD) and vascular dementia (VD); however, these findings are inconsistent. It remains unclear whether these associations are causal. METHODS: We conducted a meta-analysis by systematically searching for observational studies on the association between IBD and dementia. Mendelian randomization (MR) analysis based on summary genome-wide association studies (GWASs) was performed. Genetic correlation and Bayesian co-localization analyses were used to provide robust genetic evidence. RESULTS: Ten observational studies involving 80,565,688 participants were included in this meta-analysis. IBD was significantly associated with dementia (risk ratio [ RR] =1.36, 95% CI = 1.04-1.78; I ² = 84.8%) and VD ( RR = 2.60, 95% CI = 1.18-5.70; only one study), but not with AD ( RR = 2.00, 95% CI = 0.96-4.13; I ² = 99.8%). MR analyses did not supported significant causal associations of IBD with dementia (dementia: odds ratio [ OR] = 1.01, 95% CI = 0.98-1.03; AD: OR = 0.98, 95% CI = 0.95-1.01; VD: OR = 1.02, 95% CI = 0.97-1.07). In addition, genetic correlation and co-localization analyses did not reveal any genetic associations between IBD and dementia. CONCLUSION Our study did not provide genetic evidence for a causal association between IBD and dementia risk. The increased risk of dementia observed in observational studies may be attributed to unobserved confounding factors or detection bias.
Humans ; Mendelian Randomization Analysis ; Inflammatory Bowel Diseases/complications* ; Dementia/etiology* ; Observational Studies as Topic ; Genome-Wide Association Study