Dry eye （DE） is a prevalent multifactorial disease of the ocular surface， clinically characterized by tear film homeostasis imbalance accompanied by related ocular surface symptoms. Specifically， the tear film is a thin liquid layer of tears covering the cornea and conjunctiva through blinking， while tear film homeostasis serves as the foundation for maintaining normal ocular surface structure and function. Insufficient tear secretion and excessive tear film evaporation lead to tear hyperosmolarity and the production of inflammatory mediators， disrupting tear film homeostasis and subsequently forming DE. Additionally， cascade reactions are triggered， resulting in a "vicious cycle of DE" that exacerbates the disease severity and prolongs its duration. Therefore， for DE treatment， it is crucial to restore tear film homeostasis and terminate this vicious cycle. Traditional Chinese medicine （TCM）， which differentiates and treats DE based on systemic conditions， often achieves favorable therapeutic outcomes， offering additional treatment options for DE. Studies have demonstrated that TCM can alleviate DE by regulating tear film homeostasis and terminating the vicious cycle. This review systematically summarizes recent basic experimental research in China and abroad on TCM in alleviating DE by regulating tear film homeostasis， aiming to provide a theoretical basis for clinical treatment and an insight for research design.

ObjectiveTo establish a mouse model of particulate matter 2.5 （PM_2.5）-induced dry eye and investigate whether Chufeng Yisuntang can ameliorate the PM_2.5-induced ocular surface damage by regulating the reactive oxygen species （ROS）/p38 mitogen-activated protein kinase （p38 MAPK） signaling pathway. MethodsSixty 8-week-old male C57BL/6J mice were used. Ten were randomly selected as the control group. The remaining 50 mice received topical instillation of 1 drop （0.1 mL） of 5 g·L^-1 PM_2.5 suspension in both eyes， four times daily. Successfully modeled mice were randomized into four groups （n=10）： Model， p38 MAPK inhibitor， Chufeng Yisuntang， and combination （Chufeng Yisuntang at 7.3 g·kg^-1 + p38 MAPK inhibitor SB203580 at 5 mg·kg^-1）. Chufeng Yisuntang was administered via gavage， and the inhibitor group via intraperitoneal injection. The control and model groups received equal volumes of distilled water by gavage. All treatments lasted for 4 weeks. General conditions were dynamically observed. Tear secretion， tear film break-up time， and corneal fluorescein staining were assessed. After intervention for 4 weeks， hematoxylin and eosin （HE） staining was used to examine the histopathological changes. Enzyme-linked immunosorbent assay （ELISA） was adopted to measure serum levels of ROS， malondialdehyde （MDA）， superoxide dismutase （SOD） 1， and SOD2. Western blot and Real-time PCR were employed to determine the protein and gene levels， respectively， of p38 MAPK， B-cell lymphoma-2 （Bcl-2）， Bcl-2-associated X protein （Bax）， and cysteinyl aspartate-specific proteinase-3 （Caspase-3） in the corneal tissue. ResultsCompared with the control group， the model group exhibited reduced tear secretion volume and tear film breakup time， along with increased corneal fluorescein staining scores （P<0.01）. Compared with the model group， the Chufeng Yisuntang group， p38 MAPK inhibitor group， and combination group demonstrated increased tear secretion volume and tear film breakup time， along with decreased corneal fluorescein staining scores （P<0.01）. HE staining revealed that compared with the control group， the model group exhibited marked increases in corneal epithelial cell layers and epithelial thickness， along with reduced meibomian gland acini and intensely stained， densely packed nuclei around the acini. Compared with the model group， the Chufeng Yisuntang group， p38 MAPK inhibitor group， and combination group showed intact corneal structure， improved cell morphology， and reduced damage severity. ELISA revealed elevated ROS and MDA levels （P<0.01） and decreased SOD1 and SOD2 levels （P<0.01） in the model group compared with the control group. Compared with the model group， Chufeng Yisuntang， p38 MAPK inhibitor， and the combination lowered ROS and MDA levels （P<0.01）， while raising SOD1 and SOD2 levels （P<0.05， P<0.01）. Western blot revealed that compared with the control group， the model group exhibited increased protein levels of p38 MAPK， Bax， and Caspase-3 （P<0.01） and reduced protein level of Bcl-2 （P<0.01）. Compared with the model group， Chufeng Yisuntang， p38 MAPK inhibitor， and the combination down-regulated the protein levels of p38 MAPK， Bax， and Caspase-3 （P<0.01）， while up-regulating the protein level of Bcl-2 （P<0.01）. Compared with the Chufeng Yisuntang group， the combination group exhibited decreased protein levels of p38 MAPK， Bax， and Caspase-3 （P<0.01） and increased protein level of Bcl-2 （P<0.01）. Real-time PCR revealed that compared with the control group， the model group exhibited upregulated mRNA levels of p38 MAPK， Bax， and Caspase-3 （P<0.01）， and downregulated mRNA level of Bcl-2 （P<0.01）. Compared with the model group， Chufeng Yisuntang， p38 MAPK inhibitor， and the combination down-regulated the mRNA levels of p38 MAPK， Bax， and Caspase-3 （P<0.01）， while up-regulating the mRNA level of Bcl-2 （P<0.05， P<0.01）. Compared with the Chufeng Yisuntang group， the combination group exhibited decreased mRNA levels of p38 MAPK， Bax， and Caspase-3 expression （P<0.05， P<0.01） and increased mRNA level of Bcl-2 （P<0.01）. ConclusionChufeng Yisuntang may partially protect against PM_2.5-induced corneal injury by inhibiting the ROS/p38 MAPK pathway， enhancing antioxidant defense， and reducing epithelial apoptosis.

Background: and Purpose Ruptured intracranial aneurysms (RIA) are associated with a mortality rate of up to 40% in the Chinese population, highlighting the critical need for targeted treatment interventions for at-risk individuals. Although the impact of aldehyde dehydrogenase 2 (ALDH2) gene mutations on susceptibility to intracranial aneurysms (IA) is well documented, the potential connection between ALDH2 rs671 single-nucleotide polymorphism (SNP) and RIA remains unexplored. Given the increased prevalence of ALDH2 gene mutations among Chinese Han individuals, it is clinically relevant to investigate the link between ALDH2 rs671 SNP and IA rupture. Methods: A prospective study was conducted on 546 patients diagnosed with IA to investigate the association between ALDH2 rs671 SNP and the risk of IA rupture. Results: The ALDH2 rs671 SNP (ALDH2*2) was significantly more prevalent in patients with unruptured IA (UIA) than in those with RIA (32.56% vs. 18.58%, P=0.004). Multivariate logistic regression analysis revealed that people with the ALDH2 mutation (ALDH2*1/*2 and ALDH2*2/*2 gene type) had a significantly reduced odds ratio (OR=0.49; 95% confidence level [CI] 0.27–0.88; P=0.018) for RIAs. Age-specific subgroup analysis indicated that the ALDH2 mutation provided a stronger protective effect in individuals aged 60 years and above with IA compared to those under 60 years old (OR=0.38 vs. OR=0.52, both P<0.05). Conclusion The incidence of RIA was significantly higher in individuals with a normal ALDH2 gene (ALDH2*1/*1) than in those with an ALDH2 rs671 SNP (ALDH2*1/*2 or ALDH2*2/*2). ALDH2 rs671 SNP may serve as a protective factor against RIA in the Chinese Han population.

OBJECTIVE To analyze the quantity transfer rule in the processing of Astragalus membranaceus before and after moistening-soaking and steaming-soaking followed by cutting. METHODS Three batches of A. membranaceus decoction pieces processed through moistening-soaking and steaming-soaking followed by cutting were prepared. The HPLC overlapping fingerprints of A. membranaceus and its decoction pieces were established through the Similarity Evaluation System of Chromatographic Fingerprints of TCM （2012 edition）. Combined with the previous qualitative analysis results， the common peaks were identified， the changes of common peak area were analyzed， and the principal component analysis was carried out. The contents of calycosin-7-glucoside， astragaloside Ⅰ and astragaloside Ⅳ in A. membranaceus and its decoction pieces were determined by HPLC， and the content differences of each component in different samples were compared. RESULTS The results of fingerprint analysis showed that 17 common peaks were identified. After steaming-soaking and moistening-soaking of A. membranaceus， the proportion of common peak area in the decoction pieces changed compared with the original medicine （for example， in A. membranaceus steaming-soaking decoction pieces， the proportion of peak area of malonyl calycosin-7-glucoside and malonyl astragaloside Ⅰ decreased， while the proportion of peak area of calycosin-7-glucoside increased）. The results of principal component analysis showed that A. membranaceus， and its decoction pieces after moistening-soaking and steaming-soaking followed by cutting were all clustered into one category respectively. The results of content determination showed that， compared with A. membranaceus， the average content of calycosin-7-glucoside in A. membranaceus moistening-soaking decoction pieces was significantly reduced （P＜0.05）； the average contents of calycosin-7-glucoside and astragaloside Ⅳ in A. membranaceus steaming- soaking decoction pieces were significantly increased （P＜0.05）； there was no significant difference in the average content of astragaloside Ⅳ in A. membranaceus moistening-soaking decoction pieces and astragaloside Ⅰ in the two decoction pieces （P＞ 0.05）. CONCLUSIONS There are differences in the quantity transfer rules of A. membranaceus before and after moistening-soaking and steaming-soaking followed by cutting. Steaming-soaking followed by cutting may make the transformation of unstable components （such as malonyl calycosin-7-glucoside and malonyl astragaloside Ⅰ） more complete.

Objective To explore the risk factors of hospitalization within 24 h after birth and respiratory support in late preterm and term neonates.Methods A case-control study was conducted on 1 468 neonates with gestational ages≥34 weeks and<42 completed weeks delivered at the University-Town Hospital of Chongqing Medical University from January 2023 to March 2024.Maternal health parameters and neonatal outcomes were systematically obtained through standardized case report forms during the study period.The neonates were stratified into the hospitalization group and the non-hospitalization group based on neonatal ward admission within 24 h.For those hospitalized with infectious diseases,subgroup analysis was conducted with further categorization into respiratory support and the non-respiratory support subgroups according to ventilatory assistance requirements.The perinatal risk factors were compared between groups and subgroups,and the independent risk factors for hospitalization and the need for respiratory support within 24 h in neonates were identified.The indicators with P<0.1 in the univariate analysis were included in the multivariate logistic regression analysis,and the stepwise regression analysis was used to fit the multivariate logistic regression model.Results There were 213 cases(14.5%)in the hospitalization group and 1 255 cases(85.5%)in the non-hospitalization group.A total of 150 neonates were hospitalized due to infectious diseases,including 48 cases(32.0%)in the respiratory support subgroup and 102 cases(68.0%)in the non-respiratory support subgroup.The multivariate logistic regression analysis showed that non-regular maternal prenatal examination(OR=2.687,95%CI:1.175～6.141,P=0.019),intrauterine growth retardation(OR=2.711,95%CI:1.106～6.646,P=0.029),premature rupture of membranes(OR=1.667,95%CI:1.139～2.438,P=0.008),chorioamnionitis(OR=4.852,95%CI:2.114～11.135,P<0.001),infectious diseases in the first week before delivery(OR=1.531,95%CI:1.015～2.310,P=0.042),turbidity of amniotic fluid(OR=3.170,95%CI:2.099～4.787,P<0.001),abnormal placenta(OR=2.335,95%CI:1.202～4.534,P=0.012),complications during pregnancy(OR=2.367,95%CI:1.360～4.118,P=0.002),and the use of glucocorticoids before delivery(OR=2.744,95%CI:1.219～5.528,P=0.009)were positively correlated with hospitalization within 24 h postnatally in late preterm and term neonates.Gestational age(OR=0.693,95%CI:0.602～0.797,P<0.001),5-minute Apgar score(OR=0.026,95%CI:0.003～0.212,P=0.001),umbilical cord blood pH(OR=0.044,95%CI:0.002～0.793,P=0.034),and umbilical cord blood BE(OR=0.885,95%CI:0.823～0.823,P=0.001)were negatively correlated with it.Premature rupture of membranes(OR=0.207,95%CI:0.070～0.618,P=0.005),infectious diseases in the first week before delivery(OR=0.245,95%CI:0.070～0.854,P=0.027),5-minute Apgar score(OR=0.063,95%CI:0.008～0.526,P=0.011),and abnormal C-reactive protein of newborns(OR=0.145,95%CI:0.046～0.460,P=0.001)were negatively correlated with the need for respiratory support in neonates hospitalized due to infectious diseases.Conclusion Risk factors for neonatal hospitalization within 24 h postnatal late preterm and term are identified as irregular antenatal care,fetal growth restriction and premature rupture of membranes in late preterm and term neonates.premature rupture of membranes,antenatal maternal infections within 1 week prior to delivery and 5-minute Apgar score≥7 emerge as significant protective factors against respiratory support requirement in neonates hospitalized with infectious diseases.

Objective:To explore the diagnostic value of the macrophage activation syndrome/systemic juvenile idiopathic arthritis（MS）score in macrophage activation syndrome（MAS）associated with systemic juvenile idiopathic arthritis（sJIA），and to provide a reference for clinical work.Methods:This study was a retrospective case-control analysis，conducted on the patients initially diagnosed as sJIA-associated with MAS and admitted into the Department of Rheumatology and Immunology of Children's Hospital Affiliated to Xi 'an Jiaotong University from July 1st，2016 to June 30th，2023. All of the patients met the diagnostic criteria for patients with MAS associated with sJIA according to the 2016 European Alliance of Associations for Rheumatology（EULAR）/American College of Rheumatology（ACR）/Pediatric Rheumatology International Trials Organization（PRINTO）standards. The basic information at baseline，clinical manifestations，and auxiliary examination results were collected. The MS score was applied to re-evaluate the children diagnosed as sJIA-associated with MAS. When the MS score ≥-2.1，the possibility of sJIA with MAS was high. Thirty cases of sJIA without MAS were randomly selected as the control group.Results:There were 28 cases in the MAS group，including 13 males（46.43%）and 15 females（53.57%），with an average age of（7.51±4.01）years. Compared with the control group，the MAS group were significantly more likely to have high fever（ χ2=8.539， P=0.003），hepatomegaly（ χ2=11.621， P<0.001），splenomegaly（ χ2=11.710， P<0.001）and neurological involvement（ χ2=27.619， P<0.001），with the differences being statistically significant. Meanwhile，there were statistically significant differences between the two groups in terms of white blood cell count（ Z=-4.001， P<0.001），neutrophil count（ Z=-3.659， P<0.001），platelet count（ Z=-4.687， P<0.001），albumin level（ Z=-4.018， P<0.001），alanine aminotransferase（ Z=-3.846， P<0.001），aspartate aminotransferase（ Z=-5.932， P<0.001），lactate dehydrogenase（ Z=-6.150， P<0.001），triglycerides（ Z=-5.874， P<0.001），fibrinogen（ Z=-5.808， P<0.001），ferritin（ Z=-5.280， P<0.001），erythrocyte sedimentation rate（ Z=-3.971， P<0.001），ferritin/erythrocyte sedimentation rate（ Z=-5.433， P<0.001），reduction of two-line cells in blood（ χ2=11.408， P<0.001）and the presence of hemophagocytosis in bone marrow smears（ χ2=28.260， P<0.001）. Moreover，there was a statistically significant difference in MS scores between the two groups（ Z=-6.148， P<0.001），with higher MS scores in the MAS group. Nevertheless，this study showed the median MS scores of both groups ≥-2.1. Conclusion:The MS score was significant to a certain degree as reference for the diagnosis of MAS，and this study showed that the MS score in the MAS group was significantly higher than the control group. However，the median MS scores in both groups were no less than -2.1. This might be related to the influence of factors during the assessment，which made it necessary to optimize the cutoff values of the MS score. Therefore，prospective studies should be carried out on the role of MS score in early identification of MAS.

Lymphoma is a highly heterogeneous malignancy characterized by complex molecular regulatory mechanisms that result in significant differences in aggressiveness and prognosis across its subtypes.Gene copy number alteration(CNA)analysis,an emerging technology,has become a pivotal tool in the precision re-search and management of lymphoma.By detecting DNA deletions,amplifications,and chromosomal copy number changes,CNA analysis addresses the limitations of traditional cytogenetic techniques,enhances the ac-curacy of subtype classification,and aids in evaluating tumor heterogeneity and disease progression.This re-view provides a comprehensive summary of CNA detection methods and their applications in lymphoma,with a focus on recent advancements in the field.It offers a comparative analysis of CNA detection techniques and discusses their role in precision diagnosis,subtype classification,monitoring disease progression,predicting therapeutic resistance,and assessing prognosis.Additionally,the review explores the potential applications of CNA analysis in uncovering molecular regulatory mechanisms,optimizing therapeutic strategies,and impro-ving patient survival outcomes.

Objective:To observe the diuretic effects of Zhuling Decoction on mice with adriamycin nephropathy (ADRN); To explore its mechanism.Methods:Totally 32 SPF male C57BL/6 mice were divided into a blank group of 7 mice and a model group of 25 mice using a random number table method. ADRN model was prepared by single tail vein injection of 0.01 g/kg of amphotericin. Two weeks later, the successfully modeled mice were divided into a model group (7 mice), a furosemide group (8 mice), and a Zhuling Decoction group (8 mice). The blank group and model group mice were given equal volumes of injection water by gavage. The furosemide group was given 2.6 mg/kg of furosemide by gavage, and the Zhuling Decoction group was given 6.5 g/kg of Zhuling Decoction by gavage, once a day, for 8 consecutive weeks. Changes in body weight and urine output of mice were observed. A biochemical analyzer was used to detect 24-hour urinary protein quantification and blood potassium and SCr levels in mice. HE staining was used to observe pathological changes in mouse kidneys, and immunohistochemistry and Western blot were used to detect the homology of cyclin dependent kinase 18 (CDK18), STIP1, and the expressions of U-box protein 1 (STUB1) and aquaporin 2 (AQP2) in mouse kidney tissue cells.Results:Compared with the model group, both the furosemide and Zhuling Decoction groups exhibited increased 24-hour urine output ( P<0.05); compared with the model group and furosemide group, Zhuling Decoction group showed reduced average optical density values and protein expressions of CDK18 and AQP2 ( P<0.05) and increased STUB1 average optical density value and protein expression ( P<0.05). Conclusion:Zhuling Decoction can increase 24-hour urine output in ADRN mice, and the mechanism may be related to down-regulation of CDK18 and AQP2 protein expressions and up-regulation of STUB1 protein expression, thereby modulating the CDK18/STUB1/AQP2 pathway and reducing water reabsorption.

Objective To investigate the effects of acupoint application at Tianshu(ST25)combined with kidney-warming and spleen-invigorating therapy on clinical efficacy,intestinal function,and the expressions of Toll-like receptor 4(TLR4)and nuclear factor kappa-B(NF-κB)in patients with ulcerative colitis(UC).Methods A total of 100 UC patients with depletion and deficiency of spleen-kidney complicated with internal accumulation of pathogenic dampness syndrome,treated in the Department of Proctology,Shanghai Municipal Hospital of Traditional Chinese Medicine Affilated to Shanghai University of Traditional Chinese Medicine from June 2022 to June 2024,were selected and randomly divided into four groups(Groups A,B,C,D)using a random number table method,with 25 patients in each group.Group A received standard mesalazine treatment.Group B received Kidney-Warming and Spleen-Invigorating Formula(composed of Psoraleae Fructus,Myristicae Semen,Euodiae Fructus,Schisandrae Chinensis Fructus,Codonopsis Radix,Poria,Atractylodis Macrocephalae Rhizoma,etc.)combined with standard mesalazine treatment.Group C received acupoint application at Tianshu(the medicinal paste for application composed of Caryophylli Flos,Cinnamomi Cortex,Atractylodis Macrocephalae Rhizoma,Euodiae Fructus,Coptidis Rhizoma,etc.)combined with standard mesalazine treatment.Group D received Kidney-Warming and Spleen-Invigorating Formula+acupoint application at Tianshu+standard mesalazine treatment.All groups were treated continuously for 12 weeks.The time for disappearance of clinical symptoms was compared among the four groups.Serum immune cytokines[β-defensin-1,total immunoglobulin A(IgA),interleukin-6(IL-6),tumor necrosis factor-alpha(TNF-α)],peripheral blood levels of TLR4 and NF-κB,protein expression levels of TLR4 mRNA and NF-κB p65 mRNA in intestinal mucosal tissue,and changes in intestinal microbiota were observed before and after treatment.The clinical efficacy of the four groups was evaluated.Results(1)Compared to the other three groups,Group D had the shortest time for disappearance of clinical symptoms such as abdominal pain,diarrhea,mucopurulent bloody stools,and tenesmus(P＜0.05).The time for disappearance of various clinical symptoms in Groups B and C was similar(P＞0.05)but was shorter than that in Group A(P＜0.05).(2)After treatment,the serum levels of β-defensin-1,IgA,IL-6,and TNF-α in all four groups were significantly lower than those before treatment(P＜0.05).Post-treatment intergroup comparisons showed statistically significant differences(P＜0.01),with Group D exhibiting the greatest reduction,significantly lower than the other three groups(P＜0.05).The levels in Groups B and C were similar(P＞0.05)but were lower than those in Group A(P＜0.05).(3)After treatment,the peripheral blood levels of TLR4 and NF-κB,and the protein expression levels of TLR4 mRNA and NF-κB p65 mRNA in intestinal mucosal tissue showed a decreasing trend in all four groups(P＜0.05).Post-treatment intergroup comparison results were statistically significant(P＜0.01),with Group D showing the greatest reduction,significantly lower than the other three groups(P＜0.05).All above levels in Groups B and C were similar(P＞0.05)but were lower than those in Group A(P＜0.05).(4)After treatment,the relative contents of Bifidobacterium and Lactobacillus increased(P＜0.05),while those of Saccharomyces and Clostridium decreased(P＜0.05)in Groups B,C,and D.Post-treatment intergroup comparison results were statistically significant(P＜0.01).Group D showed a significant increase in Bifidobacterium and Lactobacillus and a significant decrease in Saccharomyces and Clostridium,with the magnitude of change significantly greater than that in the other three groups(P＜0.05).The quantities of these bacteria in Groups B and C were similar(P＞0.05),but the improvement was significantly greater than that in Group A(P＜0.05).(5)After 12 weeks of treatment,Group D had the highest total effective rate at 100.00％(25/25).The total effective rates of Groups B and C were similar,both at 84.00％(21/25),but were higher than that of Group A(56.00％,14/25).The intergroup difference was statistically significant(x2=16.310,P＜0.01).Conclusion The comprehensive treatment regimen of acupoint application at Tianshu combined with Kidney-Warming and Spleen-Invigorating Formula,on the basis of standard mesalazine treatment,has a positive impact on UC patients with depletion and deficiency of spleen-kidney complicated with internal accumulation of pathogenic dampness syndrome.This treatment method can effectively improve clinical symptoms,regulate β-defensin-1 and IgA levels,enhance immune defense function,downregulate the expression levels of TLR4 and NF-κB,and alleviate inflammatory response.Compared to monotherapies,it is more effective on improving treatment outcomes.

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*