Volume 12, Issue 1

Gastric cancer (GC) ranks third among cancers in terms of mortality rate worldwide. A clear understanding of the mechanisms underlying the genesis and progression of GC will contribute to clinical decision making. N 6 -methyladenosine (m 6 A) is the most abundant among diverse mRNA modification types and regulates multiple facets of RNA metabolism. In recent years, emerging studies have shown that m 6 A modifications are involved in gastric carcinoma tumorigenesis and progression and can potentially be valuable new prospects for diagnosis and prognosis. This article reviews the recent progress regarding m 6 A in GC.

Fibrosis occurs in many organs, and its sustained progress can lead to organ destruction and malfunction. Although numerous studies on organ fibrosis have been carried out, its underlying mechanism is largely unknown, and no ideal treatment is currently available. Ferroptosis is an iron-dependent process of programmed cell death that is characterized by lipid peroxidation. In the past decade, a growing body of evidence demonstrated the association between ferroptosis and fibrotic diseases, while targeting ferroptosis may serve as a potential therapeutic strategy. This review highlights recent advances in the crosstalk between ferroptosis and organ fibrosis, and discusses ferroptosis-targeted therapeutic approaches against fibrosis that are currently being explored.

Background and Objectives Cardiac injury plays a critical role in contributing to the mortality associated with sepsis, a condition marked by various forms of programmed cell deaths. Previous studies hinted at the WW domain-containing E3 ubiquitin protein ligase 2 (WWP2) involving in heart failure and endothelial injury. However, the precise implications of WWP2 in sepsis-induced cardiac injury, along with the underlying mechanisms, remain enigmatic. Methods Sepsis induced cardiac injury were constructed by intraperitoneal injection of lipopolysaccharide. To discover the function of WWP2 during this process, we designed and performed loss/gain-of-function studies with cardiac-specific vectors and WWP2 knockout mice. Combination experiments were performed to investigate the relationship between WWP2 and downstream signaling in septic myocardium injury. Results The protein level of WWP2 was downregulated in cardiomyocytes during sepsis. Cardiac-specific overexpression of WWP2 protected heart from sepsis induced mitochondrial oxidative stress, programmed cell death and cardiac injury, while knockdown or knockout of WWP2 exacerbated this process. The protective potency of WWP2 was predominantly linked to its ability to suppress cardiomyocyte ferroptosis rather than apoptosis. Mechanistically, our study revealed a direct interaction between WWP2 and acyl-CoA synthetase long-chain family member 4 (FACL4), through which WWP2 facilitated the ubiquitin-dependent degradation of FACL4. Notably, we observed a notable reduction in ferroptosis and cardiac injury within WWP2 knockout mice after FACL4 knockdown during sepsis. Conclusions WWP2 assumes a critical role in safeguarding the heart against injury induced by sepsis via regulating FACL4 to inhibit LPS-induced cardiomyocytes ferroptosis.

Background Mononuclear cells in peripheral blood and ascites are important clinical resources commonly used in translational and basic research. However, the impact of different cryopreservation durations and extra freeze-thaw cycles on the number and function of mononuclear cells is unknown. Methods Peripheral blood samples ( n = 21) and ascites samples ( n = 8) were collected from healthy volunteers and ovarian cancer patients. Mononuclear cells were isolated, frozen, and thawed at 6 and 12 months. The impact of cryopreservation on cell viability, the phenotype, and the activation and proliferation of T cells were analyzed by flow cytometry. Single-cell sequencing was applied to investigate the underlying mechanism. Results The cell number and viability of mononuclear cells in peripheral blood and ascites were significantly decreased after cryopreservation. The T lymphocytes, especially CD4 + T cells, were affected the most significantly. By contrast, monocytes, natural killer (NK) cells, natural killer T (NKT) cells, and B cells were more tolerant. Meanwhile, T cell proliferation and IL-2 secretion are significantly affected after long-term cryopreservation. Mechanistically, the cell death induced by elevated reactive oxygen species (ROS) was involved in the reduction of CD4 + T cells after cryopreservation. Conclusions Our data indicates that different subtypes of mononuclear cells exhibit different tolerance capacities upon cryopreservation. Thus, our research can provide evidence and support for individuals who are conducting experiments using frozen clinical patient-derived mononuclear cells, for basic research or clinical trials. In addition, extra caution is worthwhile when researchers compare immune cell functionality from peripheral blood or ascites across datasets obtained in different cryopreservation conditions.

Background and Objective Hemodynamic changes that lead to increased blood pressure represent the main drivers of organ damage in hypertension. Prolonged increases to blood pressure can lead to vascular remodeling, which also affects vascular hemodynamics during the pathogenesis of hypertension. Exercise is beneficial for relieving hypertension, however the mechanistic link between exercise training and how it influences hemodynamics in the context of hypertension is not well understood. Methods n exercise model was developed using spontaneously hypertensive rats (SHR) subject to a 12-week treadmill training regime. The heart rates and blood pressures of rats were measured using the tail cuff method, while micro-computed tomography (CT) scanning was used to develop three-dimensional structures of rat aorta, and ultrasound was used to detect rat aortic blood flow and changes to vessel wall structures. Computational fluid dynamics (CFD) and fluid-structure interaction (FSI) models were used to simulate and measure hemodynamic parameters of the rat aortic vessels. In parallel, Masson staining was performed on fixed samples of blood vessels to investigate collagen volume fraction. Hypertensive rats in the sedentary and long-term exercise training groups were subjected to a single bout exercise training, and their aortic hemodynamic parameters were analyzed before, 5 min, 24 h, and 72 h after the single bout exercise. Results Of the two models, in comparison to actual ultrasonic measurement values recorded, we found that numerical simulation results from the FSI model could more accurately model blood flow in the ascending aorta of hypertensive rats, compared to the CFD model. Moreover, longterm exercise training improved local hemodynamic parameters of blood vessels, and led to improvements in adverse hemodynamic features documented, including time-averaged wall shear stress (TAWSS), oscillatory shear index (OSI), and relative residence time (RRT). Longterm exercise training of SHR also improved local vascular collagen deposition in the aorta, while improvements in vascular remodeling were also correlated with favorable hemodynamic parameters. Compared with sedentary SHR, signals for low TAWSS regions of the aortic arch in SHR on the long-term exercise regime shifted to the position of the ascending aorta after a single bout of exercise. Conclusions This study demonstrates that FSI is informative to study the spatiotemporal effects of long-term exercise training on hemodynamic changes within the aortas of hypertensive rats, and that long-term exercise is beneficial through its effects to modulate vascular hemodynamics in hypertension.

Background The prospective relationship between plasma vitamin E levels and proteinuria remains uncertain. We aimed to evaluate the association between baseline plasma vitamin E levels and the development of proteinuria and examine any possible effect modifiers in patients with hypertension. Methods This was a post hoc analysis of the renal sub-study of the China Stroke Primary Prevention Trial (CSPPT). In total, 780 participants with vitamin E measurements and without proteinuria at baseline were included in the current study. The study outcome was the development of proteinuria, defined as a urine dipstick reading of a trace or ≥ 1+ at the exit visit. Results During a median follow-up duration of 4.4 years, the development of proteinuria occurred in 93 (11.9%) participants. Overall, there was an inverse relationship between plasma vitamin E and the development of proteinuria (per standard deviation [SD] increment; odds ratio [OR]: 0.73, 95% confidence interval [CI]: 0.55–0.96). Consistently, when plasma vitamin E was assessed as quartiles, lower risk of proteinuria development was found in participants in quartiles 2–4 (≥ 7.3 μg/mL; OR: 0.57, 95% CI: 0.34–0.96) compared to those in quartile 1. None of the variables, including sex, age, and body mass index, significantly modified the association between vitamin E and proteinuria development. Conclusion There was a significant inverse association between plasma vitamin E levels and the development of proteinuria in patients with hypertension. The results were consistent among participants with different baseline characteristics.

Background and Objectives ST-segment elevation myocardial infarction (STEMI) is the deadliest and most time-sensitive acute cardiac event. However, failure to achieve timely informed consent is an important contributor to in-hospital delay in STEMI care in China. We investigated the factors associated with informed consent delay in patients with STEMI undergoing percutaneous coronary intervention (PCI) and the association between the delay and door-to-balloon time. Methods We conducted a nationally representative retrospective cohort study using patient data reported by hospital-based chest pain centers from 1 January 2016 to 31 December 2020. We applied generalized linear mixed models and negative binomial regression to estimate factors independently predicting informed consent delay time. Logistic regressions were fitted to investigate the association of the informed consent delay time and door-to-balloon time, adjusting for patient characteristics. Results In total, 257, 510 patients were enrolled in the analysis. Mean informed consent delay time was 22.4 min (SD = 24.0), accounting for 39.3% in door-to-balloon time. Older age (≥65 years) was significantly correlated with informed consent delay time (RR: 1.034, P = 0.001). Compared with ethnic Han patients, the minority (RR: 1.146, P < 0.001) had more likelihood to extend consent giving; compared with patients who were single, longer informed consent time was found in married patients (RR: 1.054, P = 0.006). Patients with intermittent chest pain (RR: 1.034, P = 0.011), and chest pain relief (RR: 1.085, P = 0.005) were more likely to delay informed consent. As for transfer modes, EMS (RR: 1.063, P < 0.001), transfer-in (RR: 1.820, P < 0.001), and in-hospital onset (RR: 1.099, P = 0.002) all had positive correlations with informed consent delay time compared to walk-in. Informed consent delay was significantly associated with prolonged door-to-balloon time (OR: 1.002, P < 0.001). Conclusion Informed consent delay is significantly associated with the door-to-balloon time which plays a crucial role in achieving better outcomes for patients with STEMI. It is essential to shorten the delay time by identifying and intervening modifiable factors that are associated with shortening the informed consent procedure in China and other countries.

Background Natural killer (NK) cells play important immunoregulatory roles in the immune pathogenesis of severe aplastic anemia (SAA). Our previous research showed that SAA caused a decrease in T cell immunoglobulin mucin-3 (TIM3) expression on NK cells. Here we investigated the expression of surface receptors, and the cytotoxicity of peripheral TIM3 + NK and TIM3 - NK cells in patients with SAA. Methods The expressions of surface receptors and cytoplasmic protein of TIM3 + NK and TIM3 - NK cells from peripheral blood were detected by FCM. The functions of mDCs, and apoptosis rate of K562 cells after co-culture with TIM3 + NK and TIM3 - NK cells were maesured by FCM. Westren-blot was used to detect the changes of TIM3 + NK and TIM3 - NK signaling pathway proteins (AKT, P-AKT) and compare the functional activity of the two groups. Results Activating receptors NKG2D and Granzyme B were higher, while inhibiting receptors NKG2A, CD158a and CD158b were lower on TIM3 - NK cells compared with TIM3 + NK cells in patients with SAA. In SAA, the expression of CD80 and CD86 on mDCs (Myeloid dendritic cells) was significantly decreased after incubation with TIM3 - NK cells. The apoptosis rate (AR) of K562 cells was significantly increased after being incubated with TIM3 - NK cells in SAA. The level of signal pathway protein AKT of TIM3 - NK cells in SAA was similar to that of TIM3 + NK cells, and the levels of P-AKT and P-AKT/AKT ratio of TIM3 - NK cells were significantly higher than those of TIM3 + NK cells. Conclusions Therefore, TIM3 exerts its inhibitory effect on NK cells and participates in the immune pathogenesis of SAA. Low expression of TIM3 contributes to the enhancement of NK cell activity which in turn inhibits the immune activation state of SAA and improves the disease state. Our research may aid the development of new therapeutic strategies based on TIM3-NK cells infusion for the treatment of SAA.

Background Atrial fibrillation (AF) is the most common cardiac arrhythmia with severe clinical sequelae, but its genetic characteristic implicated in pathogenesis has not been completely clarified. Accumulating evidence has indicated that circulating exosomes and their carried cargoes, such as long non-coding RNAs (lncRNAs), involve in the progress of multiple cardiovascular diseases. However, their potential role as clinical biomarkers in AF diagnosis and prognosis remains unknown. Methods Herein, we conducted the sequence and bioinformatic analysis of circulating exosomes harvested from AF and sinus rhythm patients. Results A total of 53 differentially expressed lncRNAs were identified, and a total of 6 significantly changed lncRNAs (fold change > 2.0), including NR0046235, NR003045, NONHSAT167247.1, NONHSAT202361.1, NONHSAT205820.1 and NONHSAT200958.1, were verified by qRT-PCR in 215 participants. Moreover, these circulating exosome lncRNA levels were different between paroxysmal and persistent AF patients, which were dramatically associated with abnormal hemodynamics and atrial diameter. Furthermore, we observed that the area under ROC curve (AUC) of six lncRNAs combination for diagnosis of persistent AF was 80.34%. Gene ontology (GO) and Kyoto encyclopedia of genes and genomes (KEGG) enrichment pathway analysis indicated these exosome lncRNAs mainly concerning response to chemokine-chemokine receptor interaction, which induced activated inflammation and structural remodeling. In addition, increased plasma levels of CXCR3 ligands, including CXCL4, CXCL9, CXCL10 and CXCL11, were accumulated in AF patient tissues. Conclusion Our study provides the transcriptome profile revealing pattern of circulating exosome lncRNAs in atrial structural remodeling, which bring valuable insights into improving prognosis and therapeutic targets for AF.