BACKGROUND: T cell dysfunction, which includes exhaustion, anergy, and senescence, is a distinct T cell differentiation state that occurs after antigen exposure. Although T cell dysfunction has been a cornerstone of cancer immunotherapy, its potential in transplant research, while not yet as extensively explored, is attracting growing interest. Interferon regulatory factor 4 (IRF4) has been shown to play a pivotal role in inducing T cell dysfunction. METHODS: A novel ultra-low-dose combination of Trametinib and Rapamycin, targeting IRF4 inhibition, was employed to investigate T cell proliferation, apoptosis, cytokine secretion, expression of T-cell dysfunction-associated molecules, effects of mitogen-activated protein kinase (MAPK) and mammalian target of rapamycin (mTOR) signaling pathways, and allograft survival in both in vitro and BALB/c to C57BL/6 mouse cardiac transplantation models. RESULTS: In vitro , blockade of IRF4 in T cells effectively inhibited T cell proliferation, increased apoptosis, and significantly upregulated the expression of programmed cell death protein 1 (PD-1), Helios, CD160, and cytotoxic T lymphocyte-associated antigen (CTLA-4), markers of T cell dysfunction. Furthermore, it suppressed the secretion of pro-inflammatory cytokines interferon (IFN)-γ and interleukin (IL)-17. Combining ultra-low-dose Trametinib (0.1 mg·kg -1 ·day -1 ) and Rapamycin (0.1 mg·kg -1 ·day -1 ) demonstrably extended graft survival, with 4 out of 5 mice exceeding 100 days post-transplantation. Moreover, analysis of grafts at day 7 confirmed sustained IFN regulatory factor 4 (IRF4) inhibition, enhanced PD-1 expression, and suppressed IFN-γ secretion, reinforcing the in vivo efficacy of this IRF4-targeting approach. The combination of Trametinib and Rapamycin synergistically inhibited the MAPK and mTOR signaling network, leading to a more pronounced suppression of IRF4 expression. CONCLUSIONS Targeting IRF4, a key regulator of T cell dysfunction, presents a promising avenue for inducing transplant immune tolerance. In this study, we demonstrate that a novel ultra-low-dose combination of Trametinib and Rapamycin synergistically suppresses the MAPK and mTOR signaling network, leading to profound IRF4 inhibition, promoting allograft acceptance, and offering a potential new therapeutic strategy for improved transplant outcomes. However, further research is necessary to elucidate the underlying pharmacological mechanisms and facilitate translation to clinical practice.
Animals ; Mice ; Mice, Inbred BALB C ; Mice, Inbred C57BL ; Interferon Regulatory Factors/metabolism* ; Heart Transplantation/methods* ; T-Lymphocytes/immunology* ; Sirolimus/therapeutic use* ; Pyridones/therapeutic use* ; Graft Survival/drug effects* ; Pyrimidinones/therapeutic use* ; Cell Proliferation/drug effects* ; Apoptosis/drug effects* ; Male ; Signal Transduction/drug effects*

BACKGROUND: Previous evidence showed that ambient air pollution and cardiovascular mortality are related. However, there is a lack of evidence towards the modification effect of long-term lifestyle on the association between short-term ambient air pollution and death from cardiovascular events. METHOD: A total of 14,609 death from major adverse cardiovascular events (MACE) were identified among the China Kadoorie Biobank participants from 2013 to 2018. Ambient air pollution exposure including particulate matter 2.5 (PM_2.5), SO₂, NO₂, CO, and O₃ from the same period were obtained from space-time model reconstructions based on remote sensing data. Case-crossover design and conditional logistic regression was applied to estimate the effect of short-term exposure to air pollutants on MACE mortality. RESULTS: We found MACE mortality was significantly associated with PM_2.5 (relative percent increase 2.91% per 10 µg/m³ increase, 95% CI 1.32-4.53), NO₂ (5.37% per 10 µg/m³ increase, 95% CI 1.56-9.33), SO₂ (6.82% per 10 µg/m³ increase, 95% CI 2.99-10.80), and CO (2.24% per 0.1 mg/m³ increase, 95% CI 1.02-3.48). Stratified analyses indicated that drinking was associated with elevated risk of MACE mortality with NO₂ and SO₂ exposure; physical inactivity was associated with higher risk of death from MACE when exposed to PM_2.5; and people who had balanced diet had lower risk of MACE mortality when exposed to CO and NO₂. CONCLUSIONS The study results showed that short-term exposure to ambient PM_2.5, NO₂, SO₂, and CO would aggravate the risk of cardiovascular mortality, yet healthy lifestyle conduct might mitigate such negative impact to some extent.
Humans ; Cardiovascular Diseases/epidemiology* ; China/epidemiology* ; Male ; Female ; Air Pollution/adverse effects* ; Middle Aged ; Air Pollutants/analysis* ; Particulate Matter/analysis* ; Environmental Exposure/adverse effects* ; Life Style ; Aged ; Adult ; Risk Factors ; Cross-Over Studies ; East Asian People

OBJECTIVES: To investigate the effects of Naoluo Xintong Decoction (NLXTD) on proliferation of rat brain microvascular endothelial cells (BMECs) after oxygen-glucose deprivation/reoxygenation (OGD/R) injury and role of the HIF-1α/VEGF pathway in mediating its effect. METHODS: Using a BMEC model of OGD/R, we tested the effects of 10% NLXTD-medicated rat serum, alone or in combination with 2ME2 or 10% NAKL, on cell proliferation, migration, tube-forming ability and permeability using CCK-8 assay, Transwell chamber assay, tube formation assay and permeability assay. Cellular expressions of VEGF and Notch were detected using ELISA and laser confocal immunofluorescence analysis, and the expressions of HIF-1α, VEGFR2, Notch1, ERK and P-ERK1/2 proteins were detected with Western blotting. RESULTS: OGD/R injury significantly decreased viability of BMECs. NLXTD treatment of the cells with OGD/R could significantly promoted cell proliferation, migration and tube formation ability, but these effects were strongly attenuated by application of 2ME2. NLXTD treatment also significantly increased the percentages of VEGF- and Notch-positive cells in the cell models and obviously enhanced the expression levels of HIF-1α, VEGFR2, Notch1 and P-ERK1/2. CONCLUSIONS NLXTD promotes proliferation, migration, and tube formation of rat BMECs after OGD/R injury possibly by activating the HIF-1α/VEGF signaling pathway.
Animals ; Hypoxia-Inducible Factor 1, alpha Subunit/metabolism* ; Drugs, Chinese Herbal/pharmacology* ; Vascular Endothelial Growth Factor A/metabolism* ; Endothelial Cells/metabolism* ; Rats ; Cell Proliferation/drug effects* ; Signal Transduction/drug effects* ; Glucose ; Brain/blood supply* ; Cells, Cultured ; Rats, Sprague-Dawley ; Vascular Endothelial Growth Factor Receptor-2/metabolism* ; Oxygen/metabolism* ; Cell Hypoxia

Objective To analyze the relationship between the fat content of supraspinatus muscle measured by spectral CT fat-muscle material decomposition technology and the tendon tear severity(TTS)of supraspinatus,as well as shoulder joint function.Methods A total of 108 patients were prospectively selected to undergo routine MRI and spectral CT imaging of the shoulder joints.The patients were divided into normal,degenerative,partial tear,and full-thickness tear groups based on MRI findings.A fat-muscle material decomposition image was generated through spectral analysis to measure the fat content of supraspinatus muscle.The differences in fat content of supraspinatus muscle between the groups were compared,and correlation analyses were performed between the fat content of supraspinatus muscle and the clinical baseline characteristics,symptom duration,and Constant-Murley scores in patients with supraspinatus tendon tears.Results Comparison of supraspinatus muscle fat content among the four groups:the full-thickness tear group＞the partial tear group＞the degenerative group＞the normal group(P＜0.05).There was a strong positive cor-relation between the supraspinatus muscle fat content and the supraspinatus TTS(r=0.654,P＜0.05).Among patients with partial and full-thickness tears of the supraspinatus tendon,there was a moderate positive correlation between supraspinatus muscle fat content and patient age(r=0.393,P＜0.05),a weak positive correlation with gender(r=0.199,P＜0.05),with higher fat content observed in females compared to males,no significant correlation with symptom duration(r=0.037,P＞0.05),a moderate positive correla-tion with body mass index(BMI)(r=0.463,P＜0.05),and a moderate negative correlation with Constant-Murley score(r=-0.316,P＜0.05).Conclusion In patients with rotator cuff tears,the quantitative fat content of supraspinatus muscle based on spectral CT fat-muscle material decomposition technology is strongly positively correlated with rotator cuff injury degree,and is also correlated with patient age,gender,BMI,and the strength of the shoulder joint muscles and range of the motion.

Objective:To analyze the spatial-temporal epidemiological characteristics of pertussis from 2013 to 2022 in Hebei Province and to provide a reference for improving prevention and control measures.Methods:Based on the data of pertussis reported in Hebei Province during 2013-2022 to analyze the popular characteristic, the ArcGIS 10.8 software was used to construct a ring map and to perform spatial autocorrelation analysis; the SaTScan 10.1 software was used for spatial-temporal scan statistics.Results:There were 6 715 cases of the cumulative report in Hebei Province from 2013 to 2022 without death. The annual report incidence was 0.90/100 000. The overall incidence rate showed an upward trend from 2013 to 2019, and during 2020-2021, it showed a sharp decline, but in 2022, it showed a sharp increase. Summer and autumn are the peak seasons of the epidemic. The incidence was highest in age group <1 year (48.67%), and the lowest age group in age group ≥15 years (0.45%) and mainly scattered children (78.03%); the incidence about men is higher than women. Spatial autocorrelation analysis showed that the onset of pertussis has spatial clustering, and high-high clusters were found in Langfang, Baoding, and Cangzhou, the top three countries with reported incidence. The area covered by a low-low cluster was consistent with the distribution of the corresponding low-incidence areas in this study. Space-time scan detects five statistically significant areas, and three zones were concentrated in 2022.Conclusions:The incidence of pertussis in Hebei had obvious season, population, and area-specific differences. There was obvious spatiotemporal and clustering, so the control of key areas should target the characteristics of time and space.

Objective:To investigate the carriage status of Neisseria meningitidis ( Nm) among the healthy population in Hebei Province for the prevention and control of meningitis. Methods:From 2015 to 2022, throat swabs were collected from health people, which were selected by cluster random sampling in 11 cities of Hebei.The positive rate of Nm was detected by bacterial culture. The serogroups of isolated strains were identified.The laboratory detection results of Nm strains, combined with epidemiological survey data, were synthetically analyzed. Results:A total of 20 245 people were investigated; 249 strains of Nm were isolated; the overall Nm carriage rate was 1.23%. The carriage rate was significantly higher in men than in women(χ 2=28.831, P<0.05). The positive rates of Nm in different age groups were significantly different(χ 2=428.018, P<0.05), with the highest rates in the 15-19 year-old group(4.90%, 149/3 042). The positive rates of Nm were significantly different in different regions(χ 2=177.512, P<0.05), with the highest positive rate of Nm in Xingtai, Shijiazhuang, Chengde and Baoding city in sequence. Among the isolated Nm strains, ungroupable serogroups, serogroup B, serogroup C, and serogroup W accounted for 71.49%(178/249), 13.65%(34/249), 6.83%(17/249) and 4.42%(11/249), respectively. Conclusions:The carriage rate of Nm among healthy population is generally low in Hebei Province. It is recommended to continue to strengthen monitoring, pay attention to the changes and distribution characteristics of Nm, and formulate scientific and targeted prevention and control measures of meningococcal disease.

[Objective]To excavate and analyze the prescription and medication rules of Dr.XU Xiancha in treating children with external heat dampness.[Methods]Select Dr.XU Xiancha's medical records of pediatric external heat and dampness,and enter data according to items such as"name""gender""age""disease name""main symptom""tongue pulse""pathogenesis""treatment""drug composition"to establish a database of external heat and dampness medical records.By using application software such as Excel 2021,SPSS Modeler 18.0,Cytoscape,SPSS Statistics 25.0,and using frequency statistics,association rules and cluster analysis techniques,the frequency of drug use,drug meridians,four Qis and five flavors,and commonly used drug equivalence in the prescription were analyzed.A complex network analysis was conducted on all drugs to obtain the core prescription.[Results]A total of 995 prescriptions and 145 drugs were included.Among them,the top 10 high-frequency drugs ranked included Artemisiae Annuae Herba,Eupatorii Herba,Gardeniae Fructus Praeparatus,Trichosanthis Radix,Curcumae Radix,Crataegi Fructus,Galli Gigerii Endothelium Corneum,Liuyi Powder,Citri Reticulatae Pericarpium and Amomi Fructus Rotundus.The five flavors of high-frequency drug were mainly pungent,bitter and sweet,while the four Qis were mainly cold and warm.The meridians mainly belonged to the lung meridian,spleen meridian and stomach meridian.The top three in the combination of prescriptions were mainly Qi regulating drugs,heat clearing drugs and phlegm resolving drugs.Association rule analysis revealed 373 highly correlated drug pairs,including Artemisiae Annuae Herba-Eupatorii Herba,Artemisiae Annuae Herba-Gardeniae Fructus Praeparatus,and Eupatorii Herba-Gardeniae Fructus Praeparatus.Through cluster analysis,two types of drugs were obtained,among which type 1 had Artemisiae Annuae Herba,Eupatorii Herba,Gardeniae Fructus Praeparatus,Curcumae Radix,Galli Gigerii Endothelium Corneum,Trichosanthis Radix and Crataegi Fructus;Type 2 Citri Exocarpium Rubrum,Peucedani Radix.Type 1 was frequently used.The core prescription obtained from the complex network analysis results consisted of 10 drugs,including Artemisiae Annuae Herba,Eupatorii Herba,Gardeniae Fructus Praeparatus,Curcumae Radix,Galli Gigerii Endothelium Corneum,Trichosanthis Radix,Crataegi Fructus,Chrysanthemi Flos,Amomi Fructus Rotundus and Forsythiae Fructus.[Conclusion]Combined with the special physiological and pathological characteristics of children and the condition of dampness and heat in the Shao region,the clinical manifestation of summer-dampness in children is mainly caused by evil of lung,spleen and stomach.Dr.XU Xiancha's treatment of summer-damp external sensation is mainly based on the method of clearing heat and drying dampness and regulating Qi,supplemented by nourishing Yin and promoting fluid,strengthening the spleen and relieving food.

Acute cerebral infarction （ACI）， also known as ischemic stroke， is a disease with a high disability rate， which brings heavy burdens to society and families. Its pathogenesis is related to many factors， of which the inflammatory theory is one of the important mechanisms. In the early stage of ACI， microglia are activated， and the inflammatory mediators， such as interleukins and tumor necrosis factor-α （TNF-α）， released by them induce vascular endothelial cells to express adhesion molecules. The circulating leukocytes （neutrophils， monocyte-macrophages， etc.） are promoted to roll and adhere to the injured vascular endothelium， migrate and cross the blood-brain barrier， penetrate and infiltrate the brain parenchyma， and further expand the local inflammatory response by releasing a variety of proinflammatory mediators， thus exacerbating the tissue injury at the injury site and ischemic penumbra. Traditional Chinese medicine （TCM） has advantages in treating the disease. TCM believes that the occurrence of stroke is related to blood stasis caused by various reasons， which block the brain vessel. This article reviewed the research progress on the effect of activating blood therapy on inflammatory factors in patients with ACI in recent years and discussed its regulation of inflammatory factors in ACI such as interleukin-1 （IL-1）， interleukin-6 （IL-6）， interleukin-8 （IL-8）， interleukin-10 （IL-10）， TNF-α， C reactive protein （CRP）， and monocyte chemotactic protein-1 （MCP-1）， hoping to elucidate the scientific connotation of TCM treatment of ACI and lay the foundation for further research.

Objective To analyze the brucellosis epidemic and genotyping characteristics of Brucella strains isolated from Hebei Province,and to provide scientific basis for brucellosis control and prevention.Methods Descriptive epidemiological analysis (including region,population,and time distribution characteristics) was performed using individual data of human brucellosis in Hebei Province from the National Notifiable Infectious Disease Reporting Information System of China Information System for Disease Control and Prevention in 2016,Brucella strains were isolated by phase culture bottles in Brucellosis Lab from Hebei Provincial Center for Disease Control and Prevention.Multiple-locus variable-number tandem-repeat analysis (MLVA) was used to identify the genotyping characteristics of the isolates.Results There were 3 774 reported cases in 2016,and 11 cities in the province had reported the cases.The cases were found mainly in Zhangjiakou,Chengde and Tangshan.And 95.98％ (167/174) of all counties were reported brucellosis cases.Vocational high risk population was farmers and herdsmen engaged in livestock and processing of animal products,accounting for 90.22％ (3 405/3 774).Male had the highest incidence,accounting for 74.38％ (2 807/3 774).The onset time was concentrated in January-August,accounting for 83.67％ (3 161/3 774).Twenty-one strains of Brucella were isolated,twenty isolates were Brucella melitensis biovar 3,and one isolate was Brucella abortus biovar 3.Panel 1 (MLVA-8) identified three genotypes 42,43,and 114,with genotype 42 representing 85.00％ (17/20);Panel 1 + Panel 2A (MLVA-11) identified three genotypes 116,122,291,with genotype 116 representing 85.00％ (17/20),which were identified as belonging to the East Mediterranean group.Panel 1 (MLVA-8) identified the genotype 36,Panel 1 + Panel 2A (MLVA-11) identified the genotype 72 of one Brucella abortus strain.It was identified as belonging to abortus C.Conclusions The brucellosis epidemic in Hebei is relatively severe,the pathogenic bacteria is mainly Brucella melitensis.The MLVA assay is a very practical and important molecular genotyping tool,it provides a basis for tracing the source of brucellosis infection.

Activation of inflammatory responses regulates the transmission of pain pathways through an integrated network in the peripheral and central nervous systems. The immunopotentiator thymosin alpha-1 (Tα1) has recently been reported to have anti-inflammatory and neuroprotective functions in rodents. However, how Tα1 affects inflammatory pain remains unclear. In the present study, intraperitoneal injection of Tα1 attenuated complete Freund's adjuvant (CFA)-induced pain hypersensitivity, and decreased the up-regulation of pro-inflammatory cytokines (TNF-α, IL-1β, and IL-6) in inflamed skin and the spinal cord. We found that CFA-induced peripheral inflammation evoked strong microglial activation, but the effect was reversed by Tα1. Notably, Tα1 reversed the CFA-induced up-regulation of vesicular glutamate transporter (VGLUT) and down-regulated the vesicular γ-aminobutyric acid transporter (VGAT) in the spinal cord. Taken together, these results suggest that Tα1 plays a therapeutic role in inflammatory pain and in the modulation of microglia-induced pro-inflammatory cytokine production in addition to mediation of VGLUT and VGAT expression in the spinal cord.