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::Homoharringtonine (HHT) is an effective anti-inflammatory, anti-viral, and anti-tumor protein synthesis inhibitor that has been applied clinically. Here, we explored the therapeutic effects of HHT in a mouse heart transplant model.Methods::Healthy C57BL/6 mice were used to observe the toxicity of HHT in the liver, kidney, and hematology. A mouse heart transplantation model was constructed, and the potential mechanism of HHT prolonging allograft survival was evaluated using Kaplan–Meier analysis, immunostaining, and bulk RNA sequencing analysis. The HHT-T cell crosstalk was modeled ex vivo to further verify the molecular mechanism of HHT-induced regulatory T cells (Tregs) differentiation. Results::HHT inhibited the activation and proliferation of T cells and promoted their apoptosis ex vivo. Treatment of 0.5 mg/kg HHT for 10 days significantly prolonged the mean graft survival time of the allografts from 7 days to 48 days ( P <0.001) without non-immune toxicity. The allografts had long-term survival after continuous HHT treatment for 28 days. HHT significantly reduced lymphocyte infiltration in the graft, and interferon-γ-secreting CD4 + and CD8 + T cells in the spleen ( P <0.01). HHT significantly increased the number of peripheral Tregs (about 20%, P <0.001) and serum interleukin (IL)-10 levels. HHT downregulated the expression of T cell receptor (TCR) signaling pathway-related genes ( CD4, H2-Eb1, TRAT1, and CD74) and upregulated the expression of IL-10 and transforming growth factor (TGF) -β pathway-related genes and Treg signature genes ( CTLA4, Foxp3, CD74, and ICOS). HHT increased CD4 + Foxp3 + cells and Foxp3 expression ex vivo, and it enhanced the inhibitory function of inducible Tregs. Conclusions::HHT promotes Treg cell differentiation and enhances Treg suppressive function by attenuating the TCR signaling pathway and upregulating the expression of Treg signature genes and IL-10 levels, thereby promoting mouse heart allograft acceptance. These findings may have therapeutic implications for organ transplant recipients, particularly those with viral infections and malignancies, which require a more suitable anti-rejection medication.

Ferroptosis is closely associated with the progression of various diseases.There are a series of anti-ferroptosis systems in the cell,the main function of which is to eliminate lipid peroxides and inhibit the occurrence of ferropto-sis.Ubiquitination is a crucial type of post-translational protein modification which can influence the degradation,intracellular localization,or function of substrate proteins.Ubiquitination modification plays an important role in regulating key proteins in-volved in ferroptosis pathways,such as SLC7A11,GPX4,FSP1,iron metabolism-related proteins,and other critical proteins in ferroptosis pathways.This review aims to summarize the research progress on ubiquitination modification of these key proteins in ferroptosis pathways,thereby elucidating the specific role of ubiquitination in ferroptosis pathways.

Existing traditional Chinese medicine (TCM)-related databases are still insufficient in data standardization, integrity and precision, and need to be updated urgently. Herein, an Encyclopedia of Traditional Chinese Medicine version 2.0 (ETCM v2.0, http://www.tcmip.cn/ETCM2/front/#/) was constructed as the latest curated database hosting 48,442 TCM formulas recorded by ancient Chinese medical books, 9872 Chinese patent drugs, 2079 Chinese medicinal materials and 38,298 ingredients. To facilitate the mechanistic research and new drug discovery, we improved the target identification method based on a two-dimensional ligand similarity search module, which provides the confirmed and/or potential targets of each ingredient, as well as their binding activities. Importantly, five TCM formulas/Chinese patent drugs/herbs/ingredients with the highest Jaccard similarity scores to the submitted drugs are offered in ETCM v2.0, which may be of significance to identify prescriptions/herbs/ingredients with similar clinical efficacy, to summarize the rules of prescription use, and to find alternative drugs for endangered Chinese medicinal materials. Moreover, ETCM v2.0 provides an enhanced JavaScript-based network visualization tool for creating, modifying and exploring multi-scale biological networks. ETCM v2.0 may be a major data warehouse for the quality marker identification of TCMs, the TCM-derived drug discovery and repurposing, and the pharmacological mechanism investigation of TCMs against various human diseases.

Animals ; Antibodies, Neutralizing/biosynthesis* ; Antibodies, Viral/biosynthesis* ; Body Weight/immunology* ; COVID-19/virology* ; Disease Models, Animal ; Disease Progression ; Humans ; Immunohistochemistry ; Lung/virology* ; Male ; Mesocricetus ; Nasal Cavity/virology* ; RNA, Viral/immunology* ; SARS-CoV-2/pathogenicity* ; Severity of Illness Index ; Viral Load

Objective:To explore the application situation and hotspots of the Q method in the field of nursing research and provide a reference for the nursing workers in China to learn and apply the Q method.Methods:Literature retrieval was conducted based on Web of Science, and statistical analysis was conducted on the number of articles published, countries, journals, institutions, authors, highly cited papers, research directions and high-frequency co-occurrence words by using the analysis function of Web of Science and visual imaging of VOSviewer.Results:A total of 686 authors from 25 countries and 23 institutions published 326 papers in 157 journals applying the Q method in nursing research, showing an overall increasing trend. South Korea (12.27%) , the United States (7.98%) , the United Kingdom (7.06%) ranked the highest number of articles published, and China ranked the sixth (3.68%) The number of citations per article was the highest in the United Kingdom (33.78 times) , followed by Canada (19.67 times) . Psychology and health care were the most interdisciplinary subjects. The research hotspots expanded from methodological discussions to nursing education, clinical practice, psychological nursing and health promotion.Conclusions:Q method is still in its infancy in the field of nursing in China and has not been widely promoted and practiced. China's publication volume and influence are relatively weak. In the future, international exchanges and cooperation should be expanded and academic frontiers and research hotspots should be grasped to improve the level and quality of research.

OBJECTIVES: To investigate the relationship between the fatty acid-binding protein 4 (FABP4) and colorectal cancer (CRC). METHODS: Using an enzyme-linked immunosorbent assay (ELISA), we measured the expression of FABP4 in plasma of 50 patients who underwent surgery for CRC from October 2017 to May 2018 and 50 healthy controls. The content of the visceral fat area (VFA) as seen with abdominal computed tomography (CT) scanning was measured by ImageJ software. The expression levels of FABP4, E-cadherin, and Snail proteins in CRC and adjacent tissues were determined by immunohistochemistry. RESULTS: The mean concentration of plasma FABP4 of CRC patients was higher than that of the control group (22.46 vs. 9.82 ng/mL; CONCLUSIONS High LPA and VFA were risk factors for increased plasma FABP4 in CRC patients. FABP4 protein was highly expressed in CRC tissues and associated with TNM stage, differentiation, and lymph node metastasis of CRC. The level of FABP4 in CRC tissue was correlated with E-cadherin and Snail expression, suggesting that FABP4 may promote CRC progression related to epithelial-mesenchymal transition (EMT).

Objective:To explore the effect of posture management combined with incentive nursing in patients with esophageal cancer surgery.Methods:From February 2019 to February 2021, convenience sampling was used to select 90 patients with esophageal cancer who received radical surgery for esophageal cancer in a ClassⅢ Grade A hospital in Nanjing as the research object. According to the random number table method, the patients were divided into the observation group and the control group with 45 cases each. The control group conducted conventional nursing, and the observation group carried out incentive nursing combined posture management. The quality of life, sleep quality, hope level, postoperative recovery and nursing satisfaction of the two groups of patients before and after the intervention were compared.Results:After the intervention, the total score of the Quality of Life Index (QL-Index) , total score and dimension scores of Herth Hope Index (HHI) , and the score of nursing satisfaction in the observation group were all higher than those in the control group, and the differences were statistically significant ( P<0.05) . After the intervention, the total score of the Pittsburgh Sleep Quality Index (PSQI) of the observation group was lower than that of the control group, and the differences were statistically significant ( P<0.05) . After the intervention, the hospital stay, first exhaust time, and first defecation time of the observation group were lower than those of the control group, and the differences were statistically significant ( P<0.05) . Conclusions:Posture management combined with incentive nursing is applied to patients with esophageal cancer surgery, which can effectively improve the patient's quality of life, sleep quality, level of hope and nursing satisfaction, and promote the patient's postoperative recovery.

Objective:To explore the value of 3.0 T high resolution MRI (HR-MRI) in the follow-up of drug treatment in acute and non-acute ischemic stroke caused by middle cerebral artery (MCA) plaque.Methods:The perspective study enrolled patients with ischemic stroke caused by MCA stenosis from October 2012 to October 2015 in the department of Neurology and Neurosurgery of Changhai Hospital Affiliated to Naval Medical University. All the patients underwent HR-MRI and then were divided into acute and non-acute stroke groups according to the intervels of the last symptom onset to the time of HR-MRI examination. All patients were informed consent to receive antiplatelet drug and intensive lipid therapy and followed up with HR-MRI. The HR-MRI sequence including T 2WI, T 1WI and contrast-enhanced T 1WI of vessel wall, and T 2WI and DWI of brain were routinely performed. T-test of paired samples was used to evaluate the changes of stenosis rate of vascular lumen, plaque enhancement degree, plaque volume and plaque burden on HR-MRI, and the NIHSS score of nervous system and blood biochemical indicators of the patients before and after treatment. Chi square test was used to compare the difference in ischemic event recurrcence between the acute and the non-acute stroke group. Results:A total of 31 acute stroke patients and 20 non-acute stroke patients were enrolled in the study. The mean follow-up time of acute stroke group was (671.71±522.86) days. Compare with the baseline, the stenosis rate of vascular lumen ( P=0.039), plaque enhancement degree ( P<0.001), plaque volume ( P=0.024) and plaque burden ( P=0.031) were all improved after the drug treatment, the NIHSS score of nervous system was also significantly improved, and the levels of total cholesterol (TC) and low density lipoprotein cholesterol (LDL-C) in 12 patients were significantly decreased. The mean follow-up time of patients with non-acute stroke was (695.35±555.90) days. The stenosis rate of vascular lumen, plaque enhancement degree, plaque volume and plaque burden were slightly improved, but without statistical significance ( P>0.05). There were no significant changes in NIHSS score of nervous system, TC, triglyceride (TG) and LDL-C ( P>0.05), however the high density lipoprotein cholesterol (HDL-C) was significantly increased than that in the baseline ( P=0.02). During the follow-up period, no new cerebral infarction was found in the DWI images of the two groups. Six patients had transient ischemic attack (TIA) recurrence in the acute stroke group and 5 patients in the non-acute stroke group, there was no significant difference between both groups(χ 2=0.229, P= 0.632). Conclusion:HR-MRI can be used as an important evaluation method for the follow-up of MCA atherosclerotic plaque therapy. After antiplatelet therapy and intensive lipid-lowering therapy, the plaque volume and burden of MCA offending plaque, and plaque enhancement decreased in acute stroke patients but there was no significant change in non-acute patients.

Objective To investigate the ability of quantitative radiomic method based on highresolution magnetic resonance imaging (HR-MRI) to distinguish between culprit plaques and non-culprit plaques of intracranial atherosclerosis.Methods Patients with middle cerebral artery and basilar artery stenosis underwent HR-MRI in Changhai Hospital Affiliated to the Naval Medical University from September 2013 to October 2016 were analyzed retrospectively.The minimum lumen area,plaque burden,severity of luminal stenosis,intraplaque hemorrhage (IPH),enhancement rate,and 109quantitative radiomic characteristics of the culprit and non-culprit plaques were measured.For clinical features and traditional plaque morphology,multivariate logistic regression models were used to determine independent risk factors for culprit plaque.A random forest-supervised machine learning method was used to determine the radiomic characteristics of distinguishing between symptomatic plaques and asymptomatic plaques.The receiver operating characteristic (ROC) curve was constructed,and the diagnostic efficacy was described by the area under the curve (AUC).Results During the study,158 subjects were enrolled,and they aged (59.42± 11.62) years.The plaques of 75 patients were located in middle cerebral artery,and the plaques of 83 patients were located in basilar artery.There were 111 symptomatic patients and 47 asymptomatic patients.Multivariate logistic regression analysis showed that smoking (odds ratio [OR] 2.724,95％ confidence interval [CI] 1.200-6.183),IPH (OR 11.340,95％ CI 1.441-89.221),and enhancement rate (OR 6.865,95％ CI 1.052-44.802) were the independent risk factors for culprit plaques.The AUC of these three characteristics for predicting symptomatic plaques were 0.605,0.584,and 0.590,respectively.The combination of the three cloud improve the test efficacy for the intracranial atherosclerotic culprit plaques,AUC could reached 0.714.Radiomic analysis showed that 22 radiomic characteristics extracted from T-2 weighted imaging,T1 weighted imaging,and contrast-enhanced T1 weighted imaging were associated with the culprit plaques.Their AUCs were 0.801,0.835,and 0.846,respectively.After the combination of all morphological and radiomic characteristics,AUC could reach 0.976,the accuracy rate was 87.4％.However,the difference was not statistically significant compared to the combined AUC of all radiomic characteristics (0.953) (P=0.275).Conclusion Radiomic analysis could accurately distinguish between the culprit plaques and non-culprit plaques of intracranial atherosclerosis,and is superior to the traditional morphological methods.