The LEPIS-HuR-TMOD4 axis regulates hepatic cholesterol homeostasis and accelerates atherosclerosis.

BACKGROUND AND AIMS: Long noncoding RNAs (lncRNAs) play important roles in the progression of atherosclerosis. In this study, we identified an uncharacterized lncRNA, Liver Expressions by PSRC1 Induced Specifically (LEPIS). This study aimed to clarify the mechanism though which LEPIS affects atherosclerosis (AS). METHODS: The expression of LEPIS and its potential target, tropomodulin 4 (TMOD4), was increased in the livers of ApoE-/- mice fed a high-fat diet (HFD). An ApoE-/- mouse model in which LEPIS or TMOD4 was overexpressed in the liver was established. The plaque load in the aorta was assessed, plasma was collected to measure blood lipid levels, and the liver was collected to study cholesterol metabolism. RESULTS: We found that both LEPIS and TMOD4 increased the AS burden and reduced hepatic cholesterol levels. A further study revealed that LEPIS and TMOD4 affected the expression of genes related to hepatic cholesterol homeostasis, including proprotein convertase subtilisin/kexin type 9 (PCSK9) and low-density lipoprotein receptor (LDLR), which are closely related to hypercholesterolemia. Mechanistically, human antigen R (HuR), an RNA-binding protein (RBP), was shown to be critical for the regulation of TMOD4 by LEPIS. Furthermore, we found that verexpression of LEPIS promoted the shuttling of HuR from the nucleus to the cytoplasm, enhanced the stability of TMOD4 mRNA, and in turn promoted the expression of TMOD4. In addition, TMOD4 was found to affect intracellular cholesterol levels through PCSK9. CONCLUSIONS: These results suggest that the LEPIS-HuR-TMOD4 axis is a potential intervention target for dysregulated hepatic cholesterol homeostasis and AS and may provide the basis for further reductions in the circulating LDL-C concentration and arterial plaque burden.

Normothermic Ex Vivo Heart Perfusion With Exosomes From Human Umbilical Cord Mesenchymal Stem Cells Improves Graft Function in Donation After Circulatory Death Hearts.

BACKGROUND: This study aimed to investigate the cardioprotective effect of exosomes derived from human umbilical cord mesenchymal stem cells on donation after circulatory death (DCD) hearts preserved with normothermic ex vivo heart perfusion (EVHP) in a rat heart transplantation model. METHODS: Thirty-two male Lewis rats were divided into 2 groups: the control group and the exosome group. The donor-heart rats were subjected to the DCD procedure by suffering a 15-min warm ischemia injury, subsequently preserved with EVHP for 90 min, and then transplanted into recipients via abdominal heterotopic heart transplantation. Vehicle or exosome was added into the perfusate of normothermic EVHP in the control or exosome group. We evaluated left ventricular graft function, myocardial inflammation, and myocardial apoptosis of the donor heart 1.5 h after heart transplantation. Furthermore, we investigate the alternation of myocardial gene expression in the donor hearts between both groups by transcriptome sequencing. RESULTS: The treatment with exosome significantly enhanced cardiac function through increasing left ventricular developed pressure, dp/dtmax, and dp/dtmin of DCD hearts at 90 min after heart transplantation compared with the control group. The myocardial cells in the exosome group exhibited an orderly arrangement without obvious edema. Furthermore, exosome added into perfusate in the exosome group significantly attenuated the level of inflammatory response and apoptosis. Transcriptome sequencing and RT-qPCR showed the phosphoinositide 3-kinase/protein kinase B pathway was activated after exosome treatment. CONCLUSIONS: Normothermic EVHP combined with exosome can be a promising and novel DCD heart preservation strategy, alleviating myocardial ischemia-reperfusion injury in the DCD heart.

Sphingolipids: drivers of cardiac fibrosis and atrial fibrillation.

Sphingolipids (SLs) are vital constituents of the plasma membrane of animal cells and concurrently regulate numerous cellular processes. An escalating number of research have evinced that SLs assume a crucial part in the progression of tissue fibrosis, a condition for which no efficacious cure exists as of now. Cardiac fibrosis, and in particular, atrial fibrosis, is a key factor in the emergence of atrial fibrillation (AF). AF has become one of the most widespread cardiac arrhythmias globally, with its incidence continuing to mount, thereby propelling it to the status of a major public health concern. This review expounds on the structure and biosynthesis pathways of several pivotal SLs, the pathophysiological mechanisms of AF, and the function of SLs in cardiac fibrosis. Delving into the influence of sphingolipid levels in the alleviation of cardiac fibrosis offers innovative therapeutic strategies to address cardiac fibrosis and AF.

Macrophage KLF15 prevents foam cell formation and atherosclerosis via transcriptional suppression of OLR-1.

BACKGROUND: Macrophage-derived foam cells are a hallmark of atherosclerosis. Scavenger receptors, including lectin-like oxidized low-density lipoprotein (LDL) receptor-1 (OLR-1), are the principal receptors responsible for the uptake and modification of LDL, facilitating macrophage lipid load and the uptake of oxidized LDL by arterial wall cells. Krüppel-like factor 15 (KLF15) is a transcription factor that regulates the expression of genes by binding to the promoter during transcription. Therefore, this study aimed to investigate the precise role of macrophage KLF15 in atherogenesis. METHODS: We used two murine models of atherosclerosis: mice injected with an adeno-associated virus (AAV) encoding the Asp374-to-Tyr mutant version of human PCSK9, followed by 12 weeks on a high-fat diet (HFD), and ApoE-/-- mice on a HFD. We subsequently injected mice with AAV-KLF15 and AAV-LacZ to assess the role of KLF15 in the development of atherosclerosis in vivo. Oil Red O, H&E, and Masson's trichome staining were used to evaluate atherosclerotic lesions. Western blots and RT-qPCR were used to assess protein and mRNA levels, respectively. RESULTS: We determined that KLF15 expression was downregulated during atherosclerosis formation, and KLF15 overexpression prevented atherosclerosis progression. KLF15 expression levels did not affect body weight or serum lipid levels in mice. However, KLF15 overexpression in macrophages prevented foam cell formation by reducing OLR-1-meditated lipid uptake. KLF15 directly targeted and transcriptionally downregulated OLR-1 levels. Restoration of OLR-1 reversed the beneficial effects of KLF15 in atherosclerosis. CONCLUSION: Macrophage KLF15 transcriptionally downregulated OLR-1 expression to reduce lipid uptake, thereby preventing foam cell formation and atherosclerosis. Thus, our results suggest that KLF15 is a potential therapeutic target for atherosclerosis.

Hypothyroidism reduces the risk of lung cancer through oxidative stress response and the PI3K/Akt signaling pathway: An RNA-seq and Mendelian randomization study.

Hypothyroidism has been suggested to play a role in tumor progression. However, the causal association between hypothyroidism and lung cancer remains unknow. To elucidate the potential association between hypothyroidism and lung cancer risk, we employ a Mendelian randomization (MR) approach. MR was performed to analyze pooled data from the International Lung Cancer Consortium (11,348 cases and 15,861 controls; European ancestry) to determine the causal relationship between hypothyroidism and lung cancer. We used 36, 83, and 14 single nucleotide polymorphisms as instrumental variables for hypothyroidism/myxoedema, hypothyroidism, and exercise, respectively. We further investigated the mechanisms involved in transcriptome analysis using data from The Cancer Genome Atlas and Genotype-Tissue Expression database. We conducted an initial validation of intermediary factor using a two-step MR analysis. Genetically predicted hypothyroidism was significantly related to the risk of overall lung cancer, specifically the risk of lung squamous cell cancer (LSCC) but not with the risk of lung adenocarcinoma (LUAD) as assessed using the inverse-variance weighted (IVM) method. A similar causal association was found between hypothyroidism/myxoedema and the risk of lung cancer, LSCC, and LUAD. Transcriptome analysis showed that genes associated with hypothyroidism, lung cancer, and LSCC were enriched in the PI3K/Akt signaling pathway and oxidative stress response. However, genes related to hypothyroidism and LUAD did not exhibit enrichment in these pathways. Hypothyroidism was significantly associated with strenuous sports or other exercises. Moreover, genetically predicted exercise was significantly related to the risk of overall lung cancer, and LSCC, but not LUAD. We detected no horizontal pleiotropy using the MR-PRESSO and MR Egger regression intercept. Hypothyroidism was causally associated with a lower risk of lung cancer, and these effects might be mediated by the oxidative stress response and the PI3K/Akt signaling pathway. Therefore, our study suggests that the potential factors and viable etiologies of hypothyroidism that contributed to lung cancer risk deserve further investigation.

Nadir oxygen delivery during cardiopulmonary bypass in acute type A aortic dissection repair.

Background: Acute type A aortic dissection (ATAAD) is associated with high mortality. Previous studies found that maintaining a high level of oxygen delivery (DO2) could decrease the postoperative mortality, but the minimum threshold of DO2 remained unclear. The present study aimed to investigate the relationship between maintaining intraoperative DO2 ≥280 mL/(min·m2) and the 90-day postoperative mortality of ATAAD patients. Methods: The clinical data of 178 ATAAD patients who underwent Sun's procedure in our center from January 2018 to July 2022 were retrospectively analyzed in the present cohort study. The included patients were divided into hypoxic group [DO2 <280 mL/(min·m2)] and normoxic group [DO2 ≥280 mL/(min·m2)]. The primary endpoint was the 90-day all-cause mortality, and the secondary endpoints were postoperative mechanical ventilation time, the application of continuous renal replacement therapy (CRRT), brain complications, and other postoperative complications. Results: Among all the patients, a total of 23 patients died 90 days postoperatively. Compared with the hypoxic group, blood flow, hematocrit (HCT), DO2, and DO2/VO2 ratio during cardiopulmonary bypass (CPB) were significantly higher, while the need for CRRT and the 90-day mortality were significantly lower in the normoxic group. The median follow-up time was 4 months. Kaplan-Meier curve indicated that the survival rate of ATAAD patients in the normoxic group was significantly higher. Univariate cox regression analysis demonstrated that 90-day mortality was reduced by 72.1% in the normoxic group. Conclusions: Maintaining DO2 ≥280 mL/(min·m2) during CPB by increasing CPB flow and HCT level is associated with decreased 90-day mortality of ATAAD patients.

Transesophageal echocardiography-guided percutaneous closure of the patent foramen ovale only uses the sheath.

Background: Percutaneous closure of the patent foramen ovale (PFO) is primarily guided by fluoroscopy in the catheter room, during which procedure both the guidewire and sheath need to pass through the PFO. We performed PFO closure using a transesophageal echocardiography (TEE)-guided approach and only the sheath was passed through the PFO during the procedure. This study aimed to evaluate the feasibility and safety of PFO closure using this technique. Methods: A retrospective observational study was performed. A total of 117 consecutive adult patients underwent percutaneous PFO closure without fluoroscopy, under the sole guidance of TEE in our hospital between December 2018 and December 2021. The data of each patient consisted of preoperative, operative, and postoperative variables collected. The primary outcome is that the occluder was successfully released. The secondary outcomes included perioperative and follow-up transthoracic echocardiography (TTE), Headache impact test-6 (HIT-6) score and clinical symptoms. Results: Transvenous PFO closure under TEE guidance was successful in all cases. The sample consisted of 93 females and 24 males with an average age of 42.3±7.8 years. There were 28 patients with preoperative cerebral infarction [Risk of Paradoxical Embolism (RoPE) score >6 points] and 89 patients with migraine. All patients underwent a preoperative TEE to confirm the presence of PFO, and contrast-enhanced transcranial Doppler (c-TCD) acoustic contrast suggested grades 3 to 4. The average time of surgery for patients (puncture to removal of the sheath) was 32 minutes. Three cases of vagus nerve reflex manifestations during surgery and two cases of transient ventricular arrhythmia all improved after symptomatic treatment. There were no instances of metal allergy, hemolysis, or other acute vascular procedural complications. For all 89 patients with migraine, significant relief or resolution was achieved during the first six-month follow-up (P<0.001). Conclusions: As a monotherapy, percutaneous closure of PFO guided by TEE where only the sheath passes through the PFO during the operation is an effective procedure with a high success rate and a low complication rate.

Synergetic EGCG and coenzyme Q10 DSPC liposome nanoparticles protect against myocardial infarction.

At the site of myocardial infarction (MI), various phenomena such as oxidative stress and myocardial apoptosis can be observed. Both epigallocatechin gallate (EGCG) and coenzyme Q10 (CoQ10) exhibit antioxidant and anti-inflammatory effects. Macrophages have demonstrated a higher internalization rate of cationic liposomes, thereby increasing their bioavailability. This study utilized EGCG in synergy with CoQ10 as an antioxidant agent and distearyl phosphatidylcholine (DSPC) as the carrier, to create liposome nanoparticles known as CE-LNPs. The CE-LNPs exhibited favorable biocompatibility and were effectively engulfed by macrophages in vitro. In addition, the CE-LNPs effectively eradicated reactive oxygen species (ROS) in hypoxic cardiomyocytes, mitigated myocardial cell apoptosis, and sustained the functionality and proliferation of myocardial cells. The anti-apoptotic effect of the CE-LNPs was further validated through TUNEL and Annexin V FITC/PI experiments. The therapeutic efficacy of CE-LNPs was evaluated in a murine model of MI. CE-LNPs demonstrated a significant reduction in scar area in vivo, facilitating cardiac repair and improving cardiac function. These findings provide evidence that EGCG synergistically combined with CoQ10 in DSPC liposome nanoparticles offers protection against MI.

Phosphatidylethanolamine aggravates Angiotensin II-induced atrial fibrosis by triggering ferroptosis in mice.

As atrial fibrosis is the main feature of atrial structural remodeling, inhibiting atrial fibrosis is crucial to the prevention of atrial fibrillation (AF) progression. Research has shown the correlation between abnormal lipid metabolism and AF progression. However, the effect of specific lipids on atrial fibrosis remains unclear. In the present study, we applied ultra-high-performance lipidomics to analyze the lipid profiles in patients with AF and identify phosphatidylethanolamine (PE) as the differential lipid associated with AF. To detect the effect of the differential lipid on atrial fibrosis, we performed the intraperitoneal injection of Angiotensin II (Ang II) to mice to induce atrial fibrosis and supplemented PE in diets. We also treated atrial cells with PE to evaluate the cellular effect of PE. We found that PE supplementation aggravated atrial fibrosis and increased the expression of the fibrosis-related protein in vitro and in vivo. Moreover, we detected the effect of PE on the atrium. We found that PE increased oxidation products and regulated the expression of ferroptosis-related proteins, which could be alleviated by a ferroptosis inhibitor. PE increased peroxidation and mitochondrial damage in vitro, which promoted cardiomyocyte death induced by Ang II. Examination of protein expression in cardiomyocytes indicated that PE triggered ferroptosis and caused cell death to participate in myocardium fibrosis. In summary, our findings demonstrated the differential lipid profiles of AF patients and revealed the potential effect of PE on atrial remodelling, suggesting that inhibition of PE and ferroptosis might serve as a potential therapy to prevent AF progression.

Macrophage polarization states in atherosclerosis.

Atherosclerosis, a chronic inflammatory condition primarily affecting large and medium arteries, is the main cause of cardiovascular diseases. Macrophages are key mediators of inflammatory responses. They are involved in all stages of atherosclerosis development and progression, from plaque formation to transition into vulnerable plaques, and are considered important therapeutic targets. Increasing evidence suggests that the modulation of macrophage polarization can effectively control the progression of atherosclerosis. Herein, we explore the role of macrophage polarization in the progression of atherosclerosis and summarize emerging therapies for the regulation of macrophage polarization. Thus, the aim is to inspire new avenues of research in disease mechanisms and clinical prevention and treatment of atherosclerosis.

Normothermic ex vivo heart perfusion with NLRP3 inflammasome inhibitor Mcc950 treatment improves cardiac function of circulatory death hearts after transplantation.

Background: The utilization of donation after circulatory death (DCD) hearts can enlarge the donor pool. However, DCD hearts suffer from serious ischemia/reperfusion injury (IRI). Recent studies found that the activation of NLRP3 inflammasome could play a significant role in organ IRI. Mcc950, which is a novel inhibitor of the NLRP3 inflammasome, can be applied to treat various kinds of cardiovascular diseases. Therefore, we hypothesized that the treatment of mcc950 could protect DCD hearts preserved with normothermic ex vivo heart perfusion (EVHP) against myocardial IRI via inhibiting NLRP3 inflammasome in a rat heart transplantation model of DCD. Methods: Donor-heart rats were randomly divided into four groups: Control group; Vehicle group; MP-mcc950 group; and MP + PO-mcc950 group. Mcc950 was added into the perfusate of normothermic EVHP in the MP-mcc950 and MP + PO-mcc950 groups, and was injected into the left external jugular vein after heart transplantation in the MP + PO-mcc950 group. Cardiac functional assessment was performed. The level of oxidative stress, inflammatory response, apoptosis, and NLRP3 inflammasome-associated protein of donor hearts were evaluated. Results: The treatment with mcc950 significantly increased the developed pressure (DP), dP/dtmax, and dP/dtmin of the left ventricular of DCD hearts at 90 min after heart transplantation in both MP-mcc950 and MP + PO-mcc950 groups. Furthermore, mcc950 added into perfusate and injected after transplantation in both MP-mcc950 and MP + PO-mcc950 groups significantly attenuated the level of oxidative stress, inflammatory response, apoptosis, and NLRP3 inflammasome compared with the vehicle group. Conclusions: Normothermic EVHP combined with mcc950 treatment can be a promising and novel DCD heart preservation strategy, which can alleviate myocardial IRI via inhibiting NLRP3 inflammasome.

Anti-Oxidative, Anti-Apoptotic, and M2 Polarized DSPC Liposome Nanoparticles for Selective Treatment of Atherosclerosis.

Purpose: Oxidative stress is one of the main pathogenic factors of atherosclerosis. However, no antioxidants have brought positive effects on the treatment of atherosclerosis. To selectively treat atherosclerosis, various means such as antioxidation, anti-apoptosis, and M2 polarization are used. The ultimate goal is that multiple regulatory pathways can help to treat atherosclerosis. Patients and Methods: In this study, Simvastatin (SIM) as a model drug, EGCG as an antioxidant agent, and distearyl phosphatidylcholine (DSPC) as major carriers were used to make liposome nanoparticles (SE-LNPs). The cytotoxicity, phagocytosis, antioxidant, and anti-apoptotic properties of nanoparticles were tested in vitro. ApoE-/- atherosclerotic mice were treated with nanoparticles. The changes of aortic Oil red staining, blood lipid, HE, and Masson sections of the aortic root were observed. Results: SE-LNPs exhibited a sustained release profile, potentially enabling the accumulation of the majority amount of drugs at the atherosclerotic plaque. The phagocytosis effect was stronger in RAW. The anti-oxidative and anti-apoptotic effects of the formulation were verified in vitro. SE-LNPs promoted the polarization of M2 macrophages. The therapeutic effect of SE-LNPs was assessed in the ApoE-/- mice model of atherosclerosis. SE-LNPs reduced reactive oxygen species and lipids in vivo. The results of Oil red staining, blood lipid, HE, and Masson sections of the aortic root showed the recovery of the focus. Conclusion: Studies have shown that SE-LNPs could resist oxidation, and apoptosis, promote M2 polarization, and reduce blood lipids and lesions, which is a reliable and selective treatment for atherosclerosis.

Postoperative central venous pressure is associated with acute kidney injury in patients undergoing coronary artery bypass grafting.

Objective: The present study aimed to investigate the association of postoperative central venous pressure (CVP) with acute kidney injury (AKI) and mortality in patients undergoing coronary artery bypass grafting (CABG). Method: Patients who underwent CABG in the MIMIC-III database were included and divided into two groups according to the optimal cutoff value of CVP for postoperative AKI determined by the receiver operating characteristic (ROC) curves. The association of CVP with AKI and mortality was determined by multivariate regression models. A 1:1 propensity score matching (PSM) was performed to balance the influence of potential confounding factors. Results: A total of 3,564 patients were included and divided into High CVP group (CVP ≥ 10.9 mmHg) and Low CVP group (CVP < 10.9 mmHg) according to the ROC analysis. Patients in High CVP group presented with higher AKI incidence (420 (28.2%) vs. 349 (16.8), p < 0.001), in-hospital mortality (28 (1.9%) vs. 6 (0.3%), p < 0.001) and 4-year mortality (149 (15.8%) vs. 162 (11.1%), p = 0.001). Multivariate regression model showed that CVP was an independent risk factor for the postoperative AKI (OR: 1.071 (1.035, 1.109), p < 0.001), in-hospital mortality (OR: 1.187 (1.026, 1.373), p = 0.021) and 4-year mortality (HR: 1.049 (1.003, 1.096), p = 0.035). A CVP above 10.9 mmHg was significantly associated with about 50% higher risk of AKI (OR: 1.499 (1.231, 1.824), p < 0.001). After PSM, 1004 pairs of score-matched patients were generated. The multivariate logistic model showed that patients with CVP ≥ 10.9 mmHg had a significantly higher risk of AKI (OR: 1.600 (1.268, 2.018), p < 0.001) in the PSM subset. However, CVP, as a continuous or a dichotomic variable, was not independently associated with in-hospital mortality (OR: 1.202 (0.882, 1.637), p = 0.244; OR: 2.636 (0.399, 17.410), p = 0.314) and 4-year mortality (HR: 1.030 (0.974, 1.090), p = 0.297; HR: 1.262 (0.911, 1.749), p = 0.162) in the PSM dataset. Conclusion: A mean CVP ≥ 10.9 mmHg within the first 24 h after CABG was independently associated with a higher risk of postoperative AKI.

Hepatocyte-specific TMEM16A deficiency alleviates hepatic ischemia/reperfusion injury via suppressing GPX4-mediated ferroptosis.

Ischemia/reperfusion (I/R)-induced liver injury with severe cell death is a major complication of liver transplantation. Transmembrane member 16A (TMEM16A), a component of hepatocyte Ca2+-activated chloride channel, has been implicated in a variety of liver diseases. However, its role in hepatic I/R injury remains unknown. Here, mice with hepatocyte-specific TMEM16A knockout or overexpression were generated to examine the effect of TMEM16A on hepatic I/R injury. TMEM16A expression increased in liver samples from patients and mice with I/R injury, which was correlated with liver damage progression. Hepatocyte-specific TMEM16A knockout alleviated I/R-induced liver damage in mice, ameliorating inflammation and ferroptotic cell death. However, mice with hepatic TMEM16A overexpression showed the opposite phenotype. In addition, TMEM16A ablation decreased inflammatory responses and ferroptosis in hepatocytes upon hypoxia/reoxygenation insult in vitro, whereas TMEM16A overexpression promoted the opposite effects. The ameliorating effects of TMEM16A knockout on hepatocyte inflammation and cell death were abolished by chemically induced ferroptosis, whereas chemical inhibition of ferroptosis reversed the potentiated role of TMEM16A in hepatocyte injury. Mechanistically, TMEM16A interacted with glutathione peroxidase 4 (GPX4) to induce its ubiquitination and degradation, thereby enhancing ferroptosis. Disruption of TMEM16A-GPX4 interaction abrogated the effects of TMEM16A on GPX4 ubiquitination, ferroptosis, and hepatic I/R injury. Our results demonstrate that TMEM16A exacerbates hepatic I/R injury by promoting GPX4-dependent ferroptosis. TMEM16A-GPX4 interaction and GPX4 ubiquitination are therefore indispensable for TMEM16A-regulated hepatic I/R injury, suggesting that blockades of TMEM16A-GPX4 interaction or TMEM16A inhibition in hepatocytes may represent promising therapeutic strategies for acute liver injury.

Normothermic Ex Vivo Heart Perfusion with Mesenchymal Stem Cell-Derived Conditioned Medium Improves Myocardial Tissue Protection in Rat Donation after Circulatory Death Hearts.

Objective: Adopting hearts from donation after circulatory death (DCD) is a promising approach to enlarge the donor pool. Nevertheless, DCD hearts experience severe warm ischemia/reperfusion (I/R) injury. Recent studies have demonstrated that conditioned medium (CM) derived from bone marrow mesenchymal stem cells (BMSCs) has the potential of reducing organ I/R injury. Therefore, we investigated whether DCD heart preservation with normothermic ex vivo heart perfusion (EVHP) and BMSCs-CM treatment could alleviate myocardial warm I/R injury in the DCD hearts. Methods: We randomly divided donor rats into two groups: (1) DCD-Control group and (2) DCD-CM group. Before DCD heart preservation with the normothermic EVHP system for 105 minutes, rats suffered from a 25-minute warm ischemia injury in the DCD procedure. Vehicle or CM (300 µl) was added to the perfusate at the beginning of the perfusion process. The cardiac function of DCD hearts in the DCD-Control and DCD-CM groups was measured every 30 minutes. Besides, non-DCD hearts were harvested from the beating-heart rats. Results: The antibody array demonstrated that the CM contained 14 bioactive factors involved in apoptosis, inflammation, and oxidative stress. Warm ischemia injury resulted in a significant increase in the level of oxidative stress, inflammation, and apoptosis in the DCD hearts of DCD-Control group. Furthermore, compared with the DCD-Control group, CM treatment increased the developed pressure, dP/dtmax and dP/dtmin of the left ventricular in the DCD hearts during a 90-minute EVHP. Moreover, the administration of CM attenuated the level of oxidative stress, inflammation, and apoptosis in the DCD hearts of the DCD-CM group. Conclusions: Normothermic EVHP combined with CM treatment can alleviate warm I/R injury in the DCD hearts by decreasing the level of oxidative stress, inflammatory response, and apoptosis, which might alleviate the shortage of donor hearts by adopting DCD hearts.

Thymic epithelial tumors: examining the GTF2I mutation and developing a novel prognostic signature with LncRNA pairs to predict tumor recurrence.

BACKGROUND: General transcription factor IIi (GTF2I) mutations are very common in thymic epithelial tumors (TETs) and are related to a more favorable prognosis in TET patients. However, limited research has been conducted on the role of GTF2I in the tumor immune microenvironment (TIME). Further, long non-coding RNAs (lncRNAs) have been associated with the survival of patients with TETs. Therefore, this study aimed to explore the relationship between GTF2I mutations and TIME and build a new potential signature for predicting tumor recurrence in the TETs. Research data was downloaded from The Cancer Genome Atlas database and the CIBERSORT algorithm was used to evaluate TIME differences between GTF2I mutant and wild-type TETs. Relevant differentially expressed lncRNAs based on differentially expressed immune-related genes were identified to establish lncRNA pairs. We constructed a signature using univariate and multivariate Cox regression analyses. RESULTS: GTF2I is the most commonly mutated gene in TETs, and is associated with an increased number of early-stage pathological types, as well as no history of myasthenia gravis or radiotherapy treatment. In the GTF2I wild-type group, immune score and immune cell infiltrations with M2 macrophages, activated mast cells, neutrophils, plasma, T helper follicular cells, and activated memory CD4 T cells were higher than the GTF2I mutant group. A risk model was built using five lncRNA pairs, and the 1-, 3-, and 5-year area under the curves were 0.782, 0.873, and 0.895, respectively. A higher risk score was related to more advanced histologic type. CONCLUSION: We can define the GTF2I mutant-type TET as an immune stable type and the GTF2I wild-type as an immune stressed type. A signature based on lncRNA pairs was also constructed to effectively predict tumor recurrence.

Oxidative stress genes in patients with esophageal squamous cell carcinoma: construction of a novel prognostic signature and characterization of tumor microenvironment infiltration.

BACKGROUND: Oxidative stress plays an important role in the progression of various types of tumors. However, its role in esophageal squamous cell carcinoma (ESCC) has seldom been explored. This study aimed to discover prognostic markers associated with oxidative stress in ESCC to improve the prediction of prognosis and help in the selection of effective immunotherapy for patients. RESULTS: A consensus cluster was constructed using 14 prognostic differentially expressed oxidative stress-related genes (DEOSGs) that were remarkably related to the prognosis of patients with ESCC. The infiltration levels of neutrophils, plasma cells, and activated mast cells, along with immune score, stromal score, and estimated score, were higher in cluster 1 than in cluster 2. A prognostic signature based on 10 prognostic DEOSGs was devised that could evaluate the prognosis of patients with ESCC. Calculated risk score proved to be an independent clinical prognostic factor in the training, testing, and entire sets. P53 signaling pathway was highly enriched in the high-risk group. The calculated risk score was positively related to the infiltration levels of resting mast cells, memory B cells, and activated natural killer (NK) cells and negatively associated with the infiltration levels of M1 and M2 macrophages. The relationship between clinical characteristics and risk score has not been certified. The half-maximal inhibitory concentration (IC50) values for sorafenib and gefitinib were lower for patients in the low-risk group. CONCLUSION: Our prognostic signature based on 10 prognostic DEOSGs could predict the disease outcomes of patients with ESCC and had strong clinical value. Our study improves the understanding of oxidative stress in tumor immune microenvironment (TIME) and provides insights for developing improved and efficient immunotherapy strategies.