1.Facial and tongue features in traditional Chinese medicine for coronary artery stenosis warning and their association chain with cardiac biomarkers
Yu Wang ; Pengcheng Ding ; Zhentao Li ; Jiyu Zhang ; Liping Tu ; Jijie Xu ; Jiatuo Xu
Digital Chinese Medicine 2026;9(2):184-196
Objective:
To explore whether digital facial and tongue diagnostic technologies can support the assessment of coronary heart disease (CHD) patients for coronary artery stenosis severity, and examine potential associations between digital tongue diagnosis features and myocardial biomarkers.
Methods:
The TFDA-1 face and tongue diagnosis instrument and the TDAS analysis system were used to perform intelligent visual examination and analysis of the facial and tongue in CHD patients who attended the Department of Cardiology at Shanghai Baoshan Hospital of Integrated Traditional Chinese and Western Medicine between October 2, 2023 and July 31, 2024. Variables were screened using principal component analysis (PCA) and multicollinearity analysis to construct four machine learning models, including random forest, LightGBM, decision tree, and naive Bayes, for the early prediction of coronary artery stenosis severity. Model performance metrics, including sensitivity, specificity, precision, F1 score, accuracy, and the area under the receiver operating characteristic (ROC) curve (AUC), were evaluated. Visual analyses were performed using the SHapley Additive exPlanations (SHAP) interpreter and decision curve analysis. For patients after percutaneous coronary intervention (PCI), a conceptual model linking cardiac biomarkers and tongue diagnosis was constructed using the partial least squares structural equation modeling (PLS-SEM), and its validity was assessed.
Results:
A total of 459 CHD patients were enrolled and assigned to a PCI group and a non-PCI group (which comprised two subgroups: mild stenosis or less group, moderate stenosis or greater group). For sublingual vein (SV) features, the PCI group had lower SV-a and SV-b than the other groups (P < 0.01 and P < 0.05, respectively). For tongue surface features, the PCI group had significantly higher tongue body (TB)-L, TB-a, and TB-b (P < 0.05, P < 0.01, and P < 0.001, respectively), as well as higher tongue coating (TC)-a and TC-b (P < 0.01 and P < 0.001, respectively). Age, SV-a, SV-b, creatine kinase-myocardial band (CK-MB), CK, TC-a, lip-L, and lip-b were incorporated in the machine learning models. The random forest model performed best, with an AUC of 0.924, an F1 score of 0.839, precision of 0.807, accuracy of 0.864, sensitivity of 0.873, and specificity of 0.839. Decision curve analysis indicated that both LightGBM and random forest had clinical utility. PLS-SEM confirmed the pathway relationships: myocardial biomarkers → TB and myocardial biomarkers → TC (coefficient = – 0.238, t = 2.239, P = 0.025, and coefficient = – 0.270, t = 2.522, P = 0.012, respectively).
Conclusion
This study developed a noninvasive early warning model for coronary artery stenosis in patients with CHD. It applied PLS-SEM to investigate the association between post-PCI cardiac biomarkers and tongue diagnosis, and validated the proposed association chain. These findings suggest that intelligent traditional Chinese medicine (TCM) visual diagnosis integrated with modern digital technology may support CHD risk assessment and comprehensive health management.
2.Effects of different nucleus chopping methods on cornea and tear inflammatory indicators in patients with hard nucleus cataract
Li JIANG ; Lei YANG ; Yuanyuan ZHONG ; Furong LIAO ; Yumeng BAO ; Pengcheng ZHANG
International Eye Science 2025;25(6):951-957
AIM: To compare the effects of different nucleus chopping methods on the central corneal thickness, corneal endothelial cell(CEC)count and tear inflammatory indicators in patients with hard nucleus cataract.METHODS: Retrospective study. Totally 89 patients(89 eyes)with hard nucleus cataract who treated in our hospital were included from January 2020 to December 2022. According to different intraoperative nucleus chopping methods, the patients were divided into reverse prechop group(46 eyes)and phaco-chop group(43 eyes). The total effective rate of surgery and visual acuity recovery were compared between the two groups. Corneal related indicators(central corneal thickness, CEC count, CEC area), tear inflammatory indicators and tear film function [tear film break-up time(BUT), Chinese Dry Eye Questionnaire(CDEQ), Schirmer Ⅰ test(SⅠt)] were observed before and after surgery in both groups, and the degree of corneal edema was evaluated.RESULTS: The effective phaco time, phaco energy and cumulative complex energy parameters in the phaco-chop group were longer or higher than those in the reverse prechop group(P<0.05). The macular retinal thickness in the reverse prechop group at 7 d and 1 mo after surgery was thinner than that in the phaco-chop group, the central corneal thickness at 3 and 7 d after surgery was also thinner than that in the phaco-chop group, the CEC count at 3 mo after surgery was more than that in the phaco-chop group, the CEC loss rate was lower than that in the phaco-chop group, and the CEC area at 3 mo after surgery was smaller than that in the phaco-chop group(P<0.05). The levels of tear TNF-α and IL-6 at 7 d and 1 mo after surgery in the reverse prechop group were lower than those in the phaco-chop group(P<0.05). The BUT at 1 and 3 mo after surgery was longer in the reverse prechop group than that in the phaco-chop group(P<0.05). The CDEQ score in the reverse prechop group was lower than that in the phaco-chop group at 1 and 3 mo after surgery(P<0.05). The SⅠt at 1 and 3 mo after surgery was higher in the reverse prechop group compared with that in the phaco-chop group(P<0.05). The degree of corneal edema at 1 d after surgery was milder in the reverse prechop group than that in the phaco-chop group(P<0.05). CONCLUSION: Compared with phaco-chop, the application of reverse-chopper prechop combined with phacoemulsification can better reduce the ultrasonic energy in the treatment of hard nuclear cataract, and it is more conducive to reducing the postoperative inflammatory degree, improving the tear film function and relieving the corneal edema degree.
3.Comparison of decompression effects between spine endoscopy hybrid technique and uniportal endoscopic surgery in treatment of lumbar spinal stenosis with bilateral symptom
Song GUO ; Xinhua LI ; Meijun YAN ; Yanbin LIU ; Zhong LIU ; Kewei LI ; Pengcheng LIU ; Beiting ZHANG ; Qiang FU
Chinese Journal of Tissue Engineering Research 2025;29(3):517-523
BACKGROUND:Spinal canal decompression using uniportal endoscopic surgery is a new minimally invasive surgery in the treatment of lumbar spinal stenosis.However,this technique needs a steep learning curve and high requirements for surgical equipment and instruments,which limits its clinical application.We previously use the spinal endoscopy as a monitoring endoscopy and combined with unilateral biportal endoscopy to propose a hybrid technique of spinal endoscopy to achieve coaxial endoscopic operation and hands-separate operation. OBJECTIVE:To compare the clinical outcome of hybrid technique and uniportal endoscopic surgery in treatment of lumbar spinal stenosis with bilateral lower limb pain symptoms. METHODS:Ninety patients diagnosed of lumbar spinal stenosis with bilateral symptoms were included and retrospectively analyzed at First People's Hospital,Shanghai Jiao Tong University from August 2020 to August 2022.44 cases were included in group A(hybrid technique group),while 46 cases were included in group B(uniportal endoscopic surgery).The nerve decompression was observed during the surgery.Operation time,hospital stay time,and expenses were recorded in both groups.The visual analog scale scores of lower back pain and both lower extremities pain,Oswestry disability index scores of quality of life and excellent and good rate of modified Macnab criteria were recorded and compared at preoperative,postoperative 3 days,and postoperative 3 and 6 months. RESULTS AND CONCLUSION:(1)The operation time of group A was significantly shorter than that of group B(P<0.05).(2)The lower back pain and lower extremity pain of the severe side at postoperative 3 days,and 3 and 6 months were significantly relieved in both groups(P<0.05).The visual analog scale score of lower extremity pain on the mild side was significantly decreased at postoperative 3 days,3 and 6 months than preoperative score in the group A(P<0.05).The visual analog scale score of lower extremity pain on the mild side was significantly decreased at postoperative 3 days than preoperative score in the group B(P<0.05).The visual analog scale scores of lower extremity pain on the mild side at postoperative 3 and 6 months did not show significant difference than preoperative score in the group B.The comparison between the two groups showed that there was no significant difference in the visual analog scale scores of postoperative lower back pain and lower extremity pain of the severe side(P>0.05).The visual analog scale scores of lower extremity pain on the mild side in the group A were significantly lower than those of group B at postoperative 3 and 6 months(P<0.05).(3)The Oswestry disability index scores of both groups at postoperative 3 day were significantly lower than preoperative score(P<0.05),and there was no significant difference between the two groups 3 days after operation.Oswestry disability index scores of group A at postoperative 3 and 6 months were significantly decreased than preoperative score(P<0.05).The Oswestry disability index scores of group B at postoperative 3 and 6 months did not show significant differences than preoperative score(P>0.05).The comparison between the two groups showed the Oswestry disability index scores of group A were significantly lower than group B at postoperative 3 and 6 months(P<0.05).(4)The results of modified Macnab showed that the excellent and good rate of group A was significantly higher than that of group B(95%,78%,P<0.05).(5)It is indicated that the hybrid technique is a new spinal endoscopy technique,which has the advantages of less trauma and faster recovery as a minimally invasive surgery.The clinical outcome of hybrid technique is superior to that of uniportal endoscopic surgery in the treatment of lumbar spinal stenosis with bilateral symptoms.Additionally,it also has the advantages of good operational flexibility and high decompression efficiency as an open surgery.
4.Risk factors of blood transfusion in total knee revision in the United States
Xiaoyin LI ; Liangxiao BAO ; Hao XIE ; Qinfeng YANG ; Pengcheng GAO ; Jian WANG ; Zhanjun SHI
Chinese Journal of Blood Transfusion 2025;38(2):201-208
[Objective] To explore the incidence and risk factors of blood transfusion undergoing total knee revision (TKR) using a nationwide database. [Methods] A retrospective data analysis was conducted based on the Nationwide Inpatient Sample (NIS), enrolling patients who underwent TKR from 2015 to 2019 with complete information. Patients under 18 years old and those using anticoagulants, antiplatelets, antithrombotic and non-steroidal were excluded. The patients were divided into two groups based on whether they received blood transfusion or not. The demographic characteristics, length of stay (LOS), total charge of hospitalization, hospital characteristics, hospital mortality, comorbidities and perioperative complications by Wilcoxon rank test for continuous data and chi-square test for categorical data. Logistic regression was performed to identify risk factors of blood transfusion undergoing TKR. [Results] The NIS database included 63 359 patients who underwent TKR. Among them, 5 271 patients received blood transfusion, with an incidence of blood transfusion of 7.8%. There was a decrease in the incidence over the years from 2015 to 2019, dropping from 10.2% to 6.5%. TKR patients requiring transfusions had experienced longer LOS, incurred higher total medical expenses, utilized Medicare more frequently, and had increased in-hospital mortality rates (all P<0.001). Independent risk factors for blood transfusion included female gender, iron-deficiency anemia, rheumatoid disease, collagen vascular disease, chronic blood loss anemia, congestive heart failure, coagulopathy, diabetes with chronic complications, lymphoma, fluid and electrolyte disorders, peripheral vascular disorders, renal failure, valvular disease and weight loss (malnutrition). In addition, risk factors for transfusion in TKR surgery included sepsis, acute myocardial infarction, deep vein thrombosis, gastrointestinal bleeding, heart failure, pneumonia, urinary tract infection, acute renal failure, postoperative delirium, wound infection, lower limb nerve injury, hemorrhage, seroma, hematoma, wound rupture and non healing. [Conclusion] Our findings highlight the importance of recognizing the risk factors of blood transfusion in TKR and establishing corresponding clinical pathways and intervention measures to reduce the occurrence of adverse events.
5.Causal relationship between visceral adipose tissue and osteoarthritis
Pengcheng SUN ; Xiaoyun ZHANG ; Zhengpeng LI ; Yongjin LI ; Zhengang GAO ; Kunjian LI
Chinese Journal of Tissue Engineering Research 2025;29(12):2631-2640
BACKGROUND:Although obesity is associated with osteoarthritis,it remains unclear whether visceral adipose tissue has a causal relationship with osteoarthritis. OBJECTIVE:To investigate the causal relationship between visceral adipose tissue and osteoarthritis using two-sample Mendelian randomization methods. METHODS:A total of 221 single nucleotide polymorphisms strongly associated with visceral adipose tissue without linkage disequilibrium were screened from the genome-wide association study (GWAS). Pooled data for osteoarthritis were derived from a large genome-wide association analysis that included up to 826690 subjects (177517 osteoarthritis patients and 649173 controls) from nine different populations. We conducted two-sample Mendelian randomization analyses to assess the causal associations between visceral adipose tissue and early-onset any-site osteoarthritis (before age 45),any-site osteoarthritis,knee osteoarthritis,hip osteoarthritis,knee or hip osteoarthritis,spinal osteoarthritis,thumb osteoarthritis,and finger osteoarthritis. Inverse variance weighting was employed as the primary Mendelian randomization analysis method,with weighted median and MR-Egger methods used for supplementary clarification. RESULTS AND CONCLUSION:Inverse variance weighting results revealed a positive causal effect of visceral adipose tissue on eight types of osteoarthritis:early-onset any-site osteoarthritis[odds ratio (OR)=1.91,95% confidence interval (CI):1.64-2.24,P=6.04×10-16],any-site osteoarthritis (OR=1.44,95% CI:1.38-1.49,P=3.65×10-75),knee osteoarthritis (OR=1.87,95% CI:1.75-2.00,P=1.29×10-79),hip osteoarthritis (OR=1.34,95% CI:1.24-1.45,P=2.84×10-14),knee or hip osteoarthritis (OR=1.71,95% CI:1.62-1.80,P=2.97×10-83),spinal osteoarthritis (OR=1.42,95% CI:1.31-1.54,P=8.89×10-17),thumb osteoarthritis (OR=1.26,95% CI:1.10-1.44,P=6.21×10-4),and finger osteoarthritis (OR=1.29,95% CI:1.13-1.49,P=2.68×10-4). Sensitivity analyses showed no heterogeneity,pleiotropy,or outliers in the causal effects of visceral adipose tissue on the eight types of osteoarthritis. These findings indicate that visceral adipose tissue is a risk factor of osteoarthritis,and excessive visceral adipose tissue may increase the risk of osteoarthritis.
6.Liquiritin improves macrophage degradation of engulfed tumour cells by promoting the formation of phagolysosomes via NOX2/gp91phox
Caiyi YANG ; Kehan CHEN ; Yunliang CHEN ; Xuting XIE ; Pengcheng LI ; Meng ZHAO ; Junjie LIANG ; Xueqian XIE ; Xiaoyun CHEN ; Yanping CAI ; Bo XU ; Qing WANG ; Lian ZHOU ; Xia LUO
Journal of Pharmaceutical Analysis 2025;15(5):1016-1032
The incomplete degradation of tumour cells by macrophages(Mφ)is a contributing factor to tumour progression and metastasis,and the degradation function of Mφ is mediated through phagosomes and lysosomes.In our preliminary experiments,we found that overactivation of NADPH oxidase 2(NOX2)reduced the ability of Mφ to degrade engulfed tumour cells.Above this,we screened out liquiritin from Glycyrrhiza uralensis Fisch,which can significantly inhibit NOX2 activity and inhibit tumours,to elucidate that suppressing NOX2 can enhance the ability of Mφ to degrade tumour cells.We found that the tumour environment could activate the NOX2 activity in Mφ phagosomes,causing Mφ to produce excessive reactive oxygen species(ROS),thus prohibiting the formation of phagolysosomes before degradation.Conversely,inhibiting NOX2 in Mφ by liquiritin can reduce ROS and promote phagosome-lysosome fusion,therefore improving the enzymatic degradation of tumour cells after phagocytosis,and subse-quently promote T cell activity by presenting antigens.We further confirmed that liquiritin down-regulated the expression of the NOX2 specific membrane component protein gp91 phox,blocking its binding to the NOX2 cytoplasmic component proteins p67 phox and p47 phox,thereby inhibiting the activity of NOX2.This study elucidates the specific mechanism by which Mφ cannot degrade tumour cells after phagocytosis,and indicates that liquiritin can promote the ability of Mφ to degrade tumour cells by suppressing NOX2.
7.Protective Effect of Xuebijing on Lung Injury in Rats with Severe Acute Pancreatitis by Blocking FPRs/NLRP3 Inflammatory Pathway
Guixian ZHANG ; Dawei LIU ; Xia LI ; Xijing LI ; Pengcheng SHI ; Zhiqiao FENG ; Jun CAI ; Wenhui ZONG ; Xiumei ZHAO ; Hongbin LIU
Chinese Journal of Experimental Traditional Medical Formulae 2025;31(1):113-120
ObjectiveTo explore the therapeutic effect of Xuebijing injection (XBJ) on severe acute pancreatitis induced acute lung injury (SAP-ALI) by regulating formyl peptide receptors (FPRs)/nucleotide-binding oligomerization domain-like receptor 3 (NLRP3) inflammatory pathway. MethodsSixty rats were randomly divided into a sham group, a SAP-ALI model group, low-, medium-, and high-dose XBJ groups (4, 8, and 12 mL·kg-1), and a positive drug (BOC2, 0.2 mg·kg-1) group. For the sham group, the pancreas of rats was only gently flipped after laparotomy, and then the abdomen was closed, while for the remaining five groups, SAP-ALI rat models were established by retrograde injection of 5% sodium taurocholate (Na-Tc) via the biliopancreatic duct. XBJ and BOC2 were administered via intraperitoneal injection once daily for 3 d prior to modeling and 0.5 h after modeling. Blood was collected from the abdominal aorta 6 h after the completion of modeling, and the expression of interleukin (IL)-1β, IL-6, and tumor necrosis factor-α (TNF-α) in plasma was measured by enzyme-linked immunosorbent assay (ELISA). The amount of ascites was measured, and the dry-wet weight ratios of pancreatic and lung tissue were determined. Pancreatic and lung tissue was taken for hematoxylin-eosin (HE) staining to observe pathological changes and then scored. The protein expression levels of FPR1, FPR2, and NLRP3 in lung tissue were detected by the immunohistochemical method. Western blot was used to detect the expression of FPR1, FPR2, and NLRP3 in lung tissue. Real-time fluorescence quantitative polymerase chain reaction (Real-time PCR) was used to detect the mRNA expression of FPR1, FPR2, and NLRP3 in lung tissue. ResultsCompared with the sham group, the SAP-ALI model group showed significantly decreased dry-wet weight ratio of lung tissue (P<0.01), serious pathological changes of lung tissue, a significantly increased pathological score (P<0.01), and significantly increased protein and mRNA expression levels of FPR1, FPR2, and NLRP3 in lung tissue (P<0.01). After BOC2 intervention, the above detection indicators were significantly reversed (P<0.01). After treatment with XBJ, the groups of different XBJ doses achieved results consistent with BOC2 intervention. ConclusionXBJ can effectively improve the inflammatory response of the lungs in SAP-ALI rats and reduce damage. The mechanism may be related to inhibiting the expression of FPRs and NLRP3 in lung tissue, which thereby reduces IL-1β and simultaneously antagonize the release of inflammatory factors IL-6 and TNF-α.
8.Mechanism of Yantiao Prescription in Treating Lipopolysaccharide-induced Acute Lung Injury Based on Arachidonic Acid Metabolic Pathways
Pengcheng LI ; Tianyang CHEN ; Rong FANG ; Anna ZHANG ; Sijia WU ; Wei LIU ; Qian WANG
Chinese Journal of Experimental Traditional Medical Formulae 2025;31(2):101-110
ObjectiveTo clarify the anti-inflammatory and lung-protective effects of Yantiao prescription on lipopolysaccharide (LPS)-induced acute lung injury (ALI), and to explore the impact of Yantiao prescription on the metabolic pathways of arachidonic acid (AA) in vivo. MethodsThirty male C57BL/6J mice were randomly divided into the following groups based on body weight: normal group, model group, dexamethasone group (2 mg·kg-1), low-dose Yantiao prescription group (18 g·kg-1), and high-dose Yantiao prescription group (36 g·kg-1), with 6 mice in each group. The ALI mouse model was established by intraperitoneal injection of LPS. The treatment groups received oral gavage once a day for 7 consecutive days, and serum and lung tissue were collected at the end of the experiment. The content of pro-inflammatory cytokines tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6) in serum was detected by enzyme-linked immunosorbent assay (ELISA). Hematoxylin-eosin (HE) staining was used to assess lung tissue pathology. The wet/dry weight ratio (W/D) and myeloperoxidase (MPO) activity in lung tissue were measured. The content of AA metabolites in serum and lung tissue was measured by liquid chromatography triple quadrupole-mass spectrometry (LC-MS/MS). ResultsCompared with the conditions in the normal group, the content of serum pro-inflammatory cytokines TNF-α, IL-1β, and IL-6 in the model group was significantly increased (P<0.01). The alveolar structure in mice was severely damaged, with markedly thickened alveolar walls and extensive inflammatory cell infiltration. The W/D ratio and MPO activity in lung tissue were significantly increased (P<0.01). The content of AA metabolites, including prostaglandin D2 (PGD2), prostaglandin E2 (PGE2), 11(S)-hydroxy-eicosatetraenoic acid [11(S)-HETE], and 5-hydroxy-eicosatetraenoic acid (5-HETE) in serum and lung tissue was significantly increased (P<0.05), while the content of 11,12-epoxyeicosatrienoic acid (11,12-EET) and 14,15-epoxyeicosatrienoic acid (14,15-EET) in serum was significantly decreased (P<0.01). Compared with the results in the model group, the content of serum pro-inflammatory cytokines TNF-α, IL-1β, and IL-6 in the dexamethasone group, low-dose Yantiao prescription group, and high-dose Yantiao prescription group was significantly reduced (P<0.05). Mild thickening of alveolar walls, scattered inflammatory cell infiltration, and relatively intact tissue structure with improved alveolar architecture were observed. The W/D ratio and MPO activity in lung tissue were significantly reduced (P<0.01). The content of AA metabolites PGD2, PGE2, 11(S)-HETE, and 5-HETE in serum from the dexamethasone group was significantly decreased (P<0.05), while the content of 14,15-EET in serum significantly increased (P<0.01), and the content of 5-HETE in lung tissue significantly decreased (P<0.01). In the low-dose and high-dose Yantiao prescription groups, the content of AA metabolites PGD2, PGE2, 11(S)-HETE, and 5-HETE in serum and lung tissue was significantly decreased (P<0.05), while the content of 11,12-EET in both serum and lung tissue was significantly increased (P<0.05). ConclusionYantiao prescription has significant protective effects against LPS-induced ALI, which are related to its regulation of AA metabolic pathways in vivo.
9.The impact of ultrasound intervention combined with tripterygium for chocolate cyst on the ovarian function of patients
Pengcheng SUN ; Bin SHEN ; Shiqi HUANG ; Lifeng LI
Journal of Interventional Radiology 2025;34(12):1328-1332
Objective To investigate the impact of ultrasound intervention combined with tripterygium for ovarian endometriosis cyst(OEC)on the ovarian function of patients.Methods The clinical data of 107 patients with clinically-conformed OEC,who received treatment at the Yuyao Municipal People's Hospital of China from December 2022 to June 2024,were retrospectively analyzed.According to different treatment methods,the patients were divided into control group(n=53)and observation group(n=54).The patients of control group were treated with laparoscopic cystectomy,while the patients of observation group were treated with ultrasound intervention combined with tripterygium therapy.The uterine artery blood flow parameters,sex hormone levels,tumor marker levels,ovarian reserve function were compared between the two groups.Results After treatment,uterine artery blood flow parameters were decreased in both groups,the levels of uterine artery blood flow parameters in the observation group were significantly lower than those in the control group(P<0.05);the levels of sex hormones were elevated in both groups,the levels of sex hormones in the observation group were obviously higher than those in the control group(P<0.05).After treatment,the tumor-related indicators generally decreased,especially in the observation group receiving combination therapy,the levels of tumor-related indicators were significantly lower than those in the control group receiving simple surgical treatment(P<0.05),indicating that the therapeutic effect of the observation group was better than that of the control group.After treatment,the ovarian reserve function of both groups were increased when compared with their preoperative values,and the ovarian reserve function of the observation group was higher than that of the control group(P<0.05).Conclusion In treating OEC patients,ultrasound intervention combined with tripterygium can regulate the levels of sex hormones,reduce tumor marker levels,improve local uterine blood flow status,and protect ovarian reserve function.This therapy is worth promoting and applying in clinical practice.
10.Inhibition of interferon regulatory factor 4 orchestrates T cell dysfunction, extending mouse cardiac allograft survival.
Wenjia YUAN ; Hedong ZHANG ; Longkai PENG ; Chao CHEN ; Chen FENG ; Zhouqi TANG ; Pengcheng CUI ; Yaguang LI ; Tengfang LI ; Xia QIU ; Yan CUI ; Yinqi ZENG ; Jiadi LUO ; Xubiao XIE ; Yong GUO ; Xin JIANG ; Helong DAI
Chinese Medical Journal 2025;138(10):1202-1212
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
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Mice
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Mice, Inbred BALB C
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Mice, Inbred C57BL
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Interferon Regulatory Factors/metabolism*
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Heart Transplantation/methods*
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T-Lymphocytes/immunology*
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Sirolimus/therapeutic use*
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Pyridones/therapeutic use*
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Graft Survival/drug effects*
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Pyrimidinones/therapeutic use*
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Cell Proliferation/drug effects*
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Apoptosis/drug effects*
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Male
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Signal Transduction/drug effects*

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