Association between lactate to hematocrit ratio and 30-day all-cause mortality in patients with sepsis: a retrospective analysis of the Medical Information Mart for Intensive Care IV database.

Background: The lactate to hematocrit ratio (LHR) has not been assessed for predicting all-cause death in sepsis patients. This study aims to evaluate the relationship between LHR and 30-day all-cause mortality in sepsis patients. Methods: This retrospective study used the data from Medical information mart for intensive care IV (MIMIC-IV, version 2.0). Our study focused on adult sepsis patients who were initially hospitalized in the Intensive care unit (ICU). The prognostic significance of admission LHR for 30-day all-cause mortality was evaluated using a multivariate Cox regression model, ROC curve analysis, Kaplan-Meier curves, and subgroup analyses. Results: A total of 3,829 sepsis patients participated in this study. Among the cohort, 8.5% of individuals died within of 30 days (p < 0.001). The area under the curve (AUC) for LHR was 74.50% (95% CI: 71.6-77.50%), higher than arterial blood lactate (AUC = 71.30%), hematocrit (AUC = 64.80%), and shows no significant disadvantage compared to qSOFA, SOFA, and SAPS II. We further evaluated combining LHR with qSOFA score to predict mortality in sepsis patients, which shows more clinical significance. ROC curve analysis showed that 6.538 was the optimal cutoff value for survival and non-survival groups. With LHR ≥6.538 vs. LHR <6.538 (p < 0.001). Subgroup analysis showed significant interactions between LHR, age, sex, and simultaneous acute respiratory failure (p = 0.001-0.005). Conclusion: LHR is an independent predictor of all-cause mortality in sepsis patients after admission, with superior predictive ability compared to blood lactate or hematocrit alone.

Combination of androgen and estrogen improves asthma by mediating Runx3 expression.

Objective: Asthma is a chronic heterogeneous airway disease, and imbalanced T-helper type 1 (Th1) and Th2 cell-mediated inflammation contribute to its pathogenesis. Although it has been suggested that androgen and estrogen were involved in development of asthma, the underlying mechanisms remained largely unclear. Studies have demonstrated that Runx3 could promote naive CD4+ T cells to differentiate into Th1 cells. Hence, our study aimed to explore the potential regulatory mechanism of androgen and estrogen on asthma via modulating Runx3. Methods: First, clinical assessments and pulmonary function tests were conducted on 35 asthma patients and 24 healthy controls. The concentrations of androgen, estrogen, and androgen estrogen ratios were assessed in peripheral blood samples of asthma patients and healthy controls. Then, a murine asthma model was established to explore the effects of estrogen and androgen (alone or in combination) on asthma. Third, an in vitro assay was used to explore the mechanism of combination of androgen and estrogen in asthma. Results: We observed decreased androgen and increased estrogen levels in asthma patients compared with healthy controls. In mice with experimental asthma, there were increased serum concentrations of estrogen and decreased serum concentrations of androgen, intervention with combination of androgen and estrogen alleviated airway inflammations, increased Runx3 expressions and elevated Th1 differentiation. In CD4+ T cells co-cultured with bronchial epithelial cells (BECs), treatment with androgen plus estrogen combination promoted Th1 differentiation, which was mitigated by Runx3 knockdown in BECs and enhanced by Runx3 overexpression. Conclusion: These findings suggest that androgen estrogen combination modulate the Th1/Th2 balance via regulating the expression of Runx3 in BECs, thereby providing experimental evidence supporting androgen and estrogen combination as a novel therapy for asthma.

METTL3 mediates SOX5 m6A methylation in bronchial epithelial cells to attenuate Th2 cell differentiation in T2 asthma.

Objective: Asthma, a chronic inflammatory disease in which type 2 T helper cells (Th2) play a causative role in the development of T2 asthma. N6-methyladenosine (m6A) modification, an mRNA modification, and methyltransferase-like 3 (METTL3) is involved in the development of T2 asthma by inhibiting Th2 cell differentiation. Sex determining region Y-box protein 5 (SOX5) is involved in regulating T cell differentiation, but its role in T2 asthma was unclear. The objective of this study was to explore the role of METTL3 and SOX5 in T2 asthma and whether there is an interaction between the two. Materials and methods: Adults diagnosed with T2 asthma (n = 14) underwent clinical information collection and pulmonary function tests. In vivo and in vitro T2 asthma models were established using female C57BL/6 mice and human bronchial epithelial cells (HBE). The expressions of METTL3 and SOX5 were detected by Western blot and qRT-PCR and Western blot. Th2 cell differentiation was determined by flow cytometry and IL-4 level was detected by ELISA. m6A methylation level was determined by m6A quantitative assay. The relationship between METTL3 expression and clinical parameters was determined by Spearman rank correlation analysis. The function of METTL3 and SOX5 genes in asthma was investigated in vitro and in vivo. The RNA immunoprecipitation assay detected the specific interaction between METTL3 and SOX5. Results: Patients with T2 asthma displayed lower METTL3 levels compared to healthy controls. Within this group, a negative correlation was observed between METTL3 and Th2 cells, while a positive correlation was noted between METTL3 and clinical parameters as well as Th1 cells. In both in vitro and in vivo models representing T2 asthma, METTL3 levels decreased significantly, while SOX5 levels showed the opposite trend. Overexpression of METTL3 gene in HBE cells significantly inhibited Th2 cell differentiation and increased m6A methylation activity. From a mechanism perspective, low METTL3 negatively regulates SOX5 expression through m6A modification dependence, while high SOX5 expression is positively associated with T2 asthma severity. Cell transfection experiments confirmed that METTL3 regulates Th2 cell differentiation and IL-4 release through SOX5. Conclusions: Overall, our results indicate that METTL3 alleviates Th2 cell differentiation in T2 asthma by modulating the m6A methylation activity of SOX5 in bronchial epithelial cells. This mechanism could potentially serve as a target for the prevention and management of T2 asthma.

Corrigendum: LASSO-derived prognostic model predicts cancer-specific survival in advanced pancreatic ductal adenocarcinoma over 50 years of age: a retrospective study of SEER database research.

[This corrects the article DOI: 10.3389/fonc.2023.1336251.].

Silibinin Inhibits Cell Ferroptosis and Ferroptosis-Related Tissue Injuries.

Ferroptosis is involved in various tissue injuries including neurodegeneration, ischemia-reperfusion injury, and acute liver injury. Ferroptosis inhibitors exhibit promising clinical potential in the treatment of various diseases. As a traditional chemical, silymarin has been widely used in healthcare and clinical applications to treat liver injuries in which ferroptosis is involved. Silibinin is the main active ingredient of silymarin. However, the effect of silibinin on ferroptosis and ferroptosis-related diseases remains unclear. Here, we found that silibinin inhibited death in different kinds of cells caused by ferroptosis inducers including RSL3 and erastin. Moreover, silibinin alleviated lipid peroxidation induced by RSL3 without affecting the labile iron pool. Next, the antioxidant activity of silibinin was demonstrated by the DPPH assay. In vivo, silibinin strikingly relieved tissue injuries and ferroptosis in the liver and kidney of glutathione peroxidase 4 (GPX4) knockout C57 BL/6J mice. Moreover, silibinin effectively rescued renal ischemia-reperfusion, a well-known ferroptosis-related disease. In conclusion, our study revealed that silibinin effectively inhibits cell ferroptosis and ferroptosis-related tissue injuries, implicating silibinin as a potential chemical to treat ferroptosis-related diseases.

Inhibition of METTL3 alleviated LPS-induced alveolar epithelial cell apoptosis and acute lung injury via restoring neprilysin expression.

AIMS: To investigate the role and mechanisms of methyltransferase-like 3 (METTL3) in the pathogenesis of lipopolysaccharide (LPS)-induced acute lung injury (ALI). MAIN METHODS: LPS intratracheally instillation was applied in alveolar epithelial cell METTL3 conditional knockout (METTL3-CKO) mice and their wild-type littermates. In addition, METTL3 inhibitor STM2457 was used. LPS treatment on mouse lung epithelial 12 (MLE-12) cell was applied to establish an in vitro model of LPS-induced ALI. H&E staining, lung wet-to-dry ratio, and total broncho-alveolar lavage fluid (BALF) concentrations were used to evaluate lung injury. Overall, the m6A level was determined with the m6A RNA Methylation Quantification Kit and dot blot assay. Expression of METTL3 and neprilysin were measured with immunohistochemistry, immunofluorescence, immunofluorescence-fluorescence in situ hybridization, and western blot. Apoptosis was detected with TUNEL, western blot, and flow cytometry. The interaction of METTL3 and neprilysin was determined with RIP-qPCR and MeRIP. KEY FINDINGS: METTL3 expression and apoptosis were increased in alveolar epithelial cells of mice treated with LPS, and METTL3-CKO or METTL3 inhibitor STM2457 could alleviate apoptosis and LPS-induced ALI. In MLE-12 cells, LPS-Induced METTL3 expression and apoptosis. Knockdown of METTL3 alleviated, while overexpression of METTL3 exacerbated LPS-induced apoptosis. LPS treatment reduced neprilysin expression, the intervention of neprilysin expression negatively regulated apoptosis without affecting METTL3 expression, and mitigated the promoting effect of METTL3 on LPS-induced apoptosis. Additionally, METTL3 could bind to the mRNA of neprilysin, and reduce its expression. SIGNIFICANCE: Our findings revealed that inhibition of METTL3 could exert anti-apoptosis and ALI-protective effects via restoring neprilysin expression.

miR-146a-3p as a potential novel therapeutic by targeting MBD2 to mediate Th17 differentiation in Th17 predominant neutrophilic severe asthma.

Th17 (T-helper 17) cells subtype of non-T2 (non-type 2) asthma is related to neutrophilic infiltration and resistance to inhaled corticosteroids (ICS), so is also known as severe asthma. Methyl-CpG binding domain protein 2 (MBD2) regulates the differentiation of the Th17 cells, tending to show a therapeutic target in severe asthma. miR-146a-3p is associated with anti-inflammatory characteristics and immunity. Moreover, bioinformatic analysis showed that MBD2 may be a target gene of miR-146a-3p. However, the role of miR-146a-3p in the differentiation of Th17 cells via MBD2 in severe asthma remains unknown. Here, we aimed to explore how miR-146a-3p interacts with MBD2 and affects the differentiation of Th17 cells in severe asthma. First, we recruited 30 eligible healthy people and 30 patients with severe asthma to detect the expression of miR-146a-3p in peripheral blood mononuclear cells (PBMCs) by qRT-PCR. Then, we established a HDM/LPS (house dust mite/lipopolysaccharide) exposure model of bronchial epithelial cells (BECs) to evaluate the expression of miR-146a-3p, the interaction between miR-146a-3p and MBD2 using western blot and luciferase reporter analysis and the effect of miR-146a-3p regulated Th17 cells differentiation by flow cytometry in BECs in vitro. Finally, we constructed a mouse model of Th17 predominant neutrophilic severe asthma to assess the therapeutic potential of miR-146a-3p in severe asthma and the effect of miR-146a-3p regulated Th17 cells differentiation via MBD2 in vivo. Decreased miR-146a-3p expression was noted in severe asthma patients, in the BECs and in the animal severe asthma models. Moreover, we demonstrated that miR-146a-3p suppressed Th17 cells differentiation by targeting the MBD2. miR-146a-3p overexpression significantly reduced airway hyperresponsiveness, airway inflammation and airway mucus secretion, while also inhibiting Th17 cells response in vivo, which relieved severe asthma. By targeting MBD2 to suppress Th17 cells differentiation, miR-146a-3p provides a potential novel therapeutic for Th17 predominant neutrophilic severe asthma.

lncRNA CRNDE Affects Th17/IL-17A and Inhibits Epithelial-Mesenchymal Transition in Lung Epithelial Cells Reducing Asthma Signs.

Background: Asthma treatment is difficult due to disease heterogeneity and comorbidities. In addition, the development of drugs targeting the underlying mechanisms of asthma remains slow. We planned to identify the most upregulated differentially expressed long noncoding RNA in asthma to explore its regulatory patterns and pathways in asthma. Methods: We sensitized mice using a mixture of ovalbumin, house dust mites, and lipopolysaccharide to establish an asthma mouse model. We also sensitized asthma cells with TGF-ß1 in an in vitro model. We performed a microarray analysis to identify the lncRNA with the differential expression level in model mice. We applied hematoxylin and eosin and Masson's trichrome stainings to mouse tissues to quantify the tissue damage extent. Next, we assess the levels of lncRNA CRNDE, miR-29a-3p, TGF-ß1, MCL-1, E-cadherin, vimentin, and snail. We counted the percentages of Th17 cells using flow cytometry. Finally, we performed a dual-luciferase reporter assay to assess the association between lncRNA CRNDE and miR-29a-3p. Results: We successfully established asthma mouse/cell models and selected the lncRNA CRNDE for our study. Transfection of si-CRNDE reduced the degree of injury and inflammation in the mouse model and reversed the TGF-ß1-induced epithelial-mesenchymal transition (EMT) in the cell model. Moreover, the E-cadherin level was upregulated, and the levels of IL-17A, vimentin, snail, and α-SMA were downregulated. We also discovered that lncRNA CRNDE negatively regulated miR-29a-3p and that this one in turn inhibited MCL-1 in mice. After lncRNA CRNDE expression downregulation, the level of miR-29a-3p was increased, and we detected reduced levels of MCL-1 and EMTs. Conclusions: lncRNA CRNDE expression downregulation led to reduced inflammation and reduced lung damage in mice with induced asthma, it inhibited the EMTs of lung epithelial cells via the miR-29a-3p/MCL-1 pathway, and it reduced the levels of Th17/IL-17A cells to reduce asthma signs.

Different clinical characteristics of current smokers and former smokers with asthma: a cross-sectional study of adult asthma patients in China.

Smoking is a trigger for asthma, which has led to an increase in asthma incidence in China. In smokers, asthma management starts with smoking cessation. Data on predictors of smoking cessation in Chinese patients with asthma are scarce. The objective of this study was to find the differences in clinical characteristics between current smokers and former smokers with asthma in order to identify factors associated with smoking cessation. Eligible adults with diagnosed asthma and smoking from the hospital outpatient clinics (n = 2312) were enrolled and underwent a clinical evaluation, asthma control test (ACT), and pulmonary function test. Information on demographic and sociological data, lung function, laboratory tests, ACT and asthma control questionnaire (ACQ) scores was recorded. Patients were divided into a current smokers group and a former smokers group based on whether they had quit smoking. Logistic regression analysis was used to analyze the factors associated with smoking cessation. Of all patients with asthma, 34.6% were smokers and 65.4% were former smokers, and the mean age was 54.5 ± 11.5 years. Compared with current smokers, the former smokers were older, had longer duration of asthma, had higher ICS dose, had more partially controlled and uncontrolled asthma, had more pack-years, had smoked for longer, and had worse asthma control. The logistic regression model showed that smoking cessation was positively correlated with age, female sex, pack-years, years of smoking, partially controlled asthma, uncontrolled asthma, and body mass index (BMI), but was negatively correlated with ACT, FEV1, FEV1%predicted, and widowed status. More than 30% of asthma patients in the study were still smoking. Among those who quit smoking, many quit late, often not realizing they need to quit until they have significant breathing difficulties. The related factors of smoking cessation identified in this study indicate that there are still differences between continuing smokers and former smokers, and these factors should be focused on in asthma smoking cessation interventions to improve the prognosis of patients with asthma.

LASSO-derived prognostic model predicts cancer-specific survival in advanced pancreatic ductal adenocarcinoma over 50 years of age: a retrospective study of SEER database research.

Background: This study aimed to develop a prognostic model for patients with advanced ductal adenocarcinoma aged ≥50 years. Methods: Patient information was extracted from the Surveillance, Epidemiology, and End Results (SEER) database. Least absolute shrinkage and selection operator (LASSO) Cox regression analysis was performed to screen the model variables. Cases from Nanchang Central Hospital were collected for external validation. The new nomogram and the American Joint Committee on Cancer (AJCC) criteria were evaluated using integrated discrimination improvement (IDI) and net reclassification index (NRI) indicators. Survival curves presented the prognosis of the new classification system and AJCC criteria. Results: In total, 17,621 eligible patients were included. Lasso Cox regression selected 4 variables including age, chemotherapy, radiotherapy and AJCC stage. The C-index of the training cohort was 0.721. The C-index value of the validation cohort was 0.729. The AUCs for the training cohorts at 1, 2, and 3 years were 0.749, 0.729, and 0.715, respectively. The calibration curves showed that the predicted and actual probabilities at 1, 2, and 3 years matched. External validation confirmed the model's outstanding predictive power. Decision curve analysis indicated that the clinical benefit of the nomogram was higher than that of the AJCC staging system. The model evaluation indices preceded the AJCC staging with NRI (1-year: 0.88, 2-year: 0.94, 3-year: 0.72) and IDI (1-year: 0.24, 2-year: 0.23, 3-year: 0.22). The Kaplan-Meier curves implied that the new classification system was more capable of distinguishing between patients at different risks. Conclusions: This study established a prognostic nomogram and risk classification system for advanced pancreatic cancer in patients aged ≥50 years to provide a practical tool for the clinical management of patients with pancreatic ductal adenocarcinoma.

MBD2 mediates Th17 cell differentiation by regulating MINK1 in Th17-dominant asthma.

Objectives: .Asthma is a highly heterogeneous disease, and T-helper cell type 17 (Th17) cells play a pathogenic role in the development of non-T2 severe asthma. Misshapen like kinase 1 (MINK1) is involved in the regulation of Th17 cell differentiation, but its effect on severe asthma remains unclear. Our previous studies showed that methyl-CpG binding domain protein 2 (MBD2) expression was significantly increased in patients with Th17 severe asthma and could regulate Th17 cell differentiation. The aim of this study was to investigate how MBD2 interacts with MINK1 to regulate Th17 cell differentiation in Th17-dominant asthma. Materials and methods: Female C57BL/6 mice and bronchial epithelial cells (BECs) were used to establish mouse and cell models of Th17-dominant asthma, respectively. Flow cytometry was used to detect Th17 cell differentiation, and the level of IL-17 was detected by enzyme-linked immunosorbent assay (ELISA). Western blot and quantitative real-time PCR (qRT-PCR) were used to detect MBD2 and MINK1 expression. To investigate the role of MBD2 and MINK1 in Th17 cell differentiation in Th17-dominant asthma, the MBD2 and MINK1 genes were silenced or overexpressed by small interfering RNA and plasmid transfection. Results: Mouse and BEC models of Th17-dominant asthma were established successfully. The main manifestations were increased neutrophils in BALF, airway hyperresponsiveness (AHR), activated Th17 cell differentiation, and high IL-17 levels. The expression of MBD2 in lung tissues and BECs from the Th17-dominant asthma group was significantly increased, while the corresponding expression of MINK1 was significantly impaired. Through overexpression or silencing of MBD2 and MINK1 genes, we have concluded that MBD2 and MINK1 regulate Th17 cell differentiation and IL-17 release. Interestingly, MBD2 was also found to negatively regulate the expression of MINK1. Conclusion: Our findings have revealed new roles for MBD2 and MINK1, and provide new insights into epigenetic regulation of Th17-dominant asthma, which is dominated by neutrophils and Th17 cells. This study could lead to new therapeutic targets for patients with Th17-dominant asthma.

Androgen Plays a Potential Novel Hormonal Therapeutic Role in Th17 Cells Predominant Neutrophilic Severe Asthma by Attenuating BECs Regulated Th17 Cells Differentiation via MBD2 Expression.

T helper 17 (Th17) cells subtype of non-T2 asthma is less responsive (resistant) to inhaled corticosteroids (ICS), so also called severe asthma. Methyl-CpG-binding domain protein 2 (MBD2) regulates the differentiation of the Th17 cells, showing the possibility of a therapeutic target in severe asthma. Androgen tends to show beneficial therapeutic effects and is a "hot research topic," but its role in the differentiation and expression of Th17 cells via MBD2 is still unknown. The aim of this study was to evaluate how sex hormone interacts with MBD2 and affects the differentiation and expression of Th17 cells in severe asthma. Here, first, we measured the concentration of androgen, estrogen, and androgen estrogen ratio from subjects and correlated it with severe asthma status. Then, we established an animal model and bronchial epithelial cells (BECs) model of severe asthma to evaluate the role of MBD2 in the differentiation and expression of Th17 cells (IL-17), the therapeutic potential of sex hormones in severe asthma, and the effect of sex hormones in BECs regulated Th17 cells differentiation via MBD2 at the cellular level. Increased MBD2 expression and Th17 cells differentiation were noted in the animal and the BECs severe asthma models. Th17 cell differentiation and expression were MBD2 dependent. Androgen attenuated the differentiation of BECs regulated Th17 cells via MBD2 showing BECs as a therapeutic target of androgen, and these findings postulate the novel role of androgen in Th17 cells predominant neutrophilic severe asthma therapy through targeting MBD2.

Effect of modified Total Body Recumbent Stepper training on exercise capacity and thioredoxin in COPD: a randomized clinical trial.

Exercise intolerance is one of the major symptoms of chronic obstructive pulmonary disease (COPD). Exercise training can benefit COPD patients, but the underlying mechanism remains unclear. The modified Total Body Recumbent Stepper (TBRS, Nustep-T4) can benefit patients with stroke, spinal cord injury and amyotrophic lateral sclerosis. Nevertheless, the effect of TBRS training alone on pulmonary rehabilitation (PR) in COPD patients remains largely unknown. We aimed to explore the effect of TBRS training on exercise capacity and the thioredoxin system (TRXS) in COPD patients to provide a novel rehabilitation modality and new theoretical basis for PR of COPD patients. Ninety stable COPD patients were randomly divided into a control group (NC group) and a TBRS training group (TBRS group), with 45 cases in each group. Subjects in the TBRS training group were scheduled to undergo TBRS endurance training triweekly for 12 weeks under the guidance of a rehabilitation therapist. We assessed the primary outcome: exercise capacity (6-min walking distance, 6MWD); and secondary outcomes: perception of dyspnoea (mMRC, Borg), the COPD assessment test (CAT), the BODE index, pulmonary function, the number of acute exacerbations of COPD and oxidative stress (TRXS) at one-year follow-up. Compared with before the intervention and the control group, after the intervention, the TBRS training group, exhibited an increase in the 6MWD (from 366.92 ± 85.81 to 484.10 ± 71.90, 484.10 ± 71.90 vs 370.63 ± 79.87, P < 0.01), while the scores on the BORG, mMRC, BODE index, CAT, and the number of acute exacerbations of COPD were reduced, and the protein and mRNA expression levels of TRXS was significantly increased (P < 0.01). However, no differences were found in PF parameters in the comparison with before the intervention or between groups. TBRS training can effectively increase exercise capacity, while there are indications that it can alleviate COPD-related dyspnoea and reduce the number of acute exacerbations of COPD. Interestingly, long-term regular TBRS training may reduce oxidative stress associated with COPD to increase exercise capacity.

Loss of MBD2 ameliorates LPS-induced alveolar epithelial cell apoptosis and ALI in mice via modulating intracellular zinc homeostasis.

Apoptosis of alveolar epithelial cells is a critical initial link in the pathogenesis of acute lung injury (ALI), recent studies have revealed that Methyl-CpG binding domain protein 2 (MBD2) was involved in the execution of apoptosis, yet its role in ALI remained unclear. In the present study, we aim to explore the role and mechanism of MBD2 in the pathogenesis of ALI. We have found that MBD2 expression, in parallel to apoptosis, increased in alveolar epithelial cells of mice treated with LPS, knockout of MBD2 reduced apoptosis and protected mice from LPS-induced ALI. In MLE-12 cells, a cell line of murine alveolar epithelial cells, LPS induced MBD2 expression and apoptosis in a dose- and time-dependent manner. Knockdown of MBD2 with shRNA alleviated, while overexpression of MBD2 increased LPS-induced apoptosis. Mechanistically, intracellular zinc level decreased when MLE-12 cells were treated with LPS. MBD2 knockdown restored intracellular zinc level after LPS treatment, and MBD2 overexpression further aggravated LPS-induced intracellular zinc loss. Metal transcription factor 1 (MTF1) is a critical transcription factor in charge of intracellular zinc efflux. LPS treatment induced MTF1 expression both in vivo and in vitro. Inhibition of MTF1 reduced LPS-induced apoptosis in MLE-12 cells. MBD2 could bind to the promoter region of MTF1 and promote MTF1 expression. Collectively, these data indicated that loss of MBD2-ameliorated LPS-induced alveolar epithelial cell apoptosis and ALI in mice via modulating intracellular zinc homeostasis by upregulating MTF1.

ß-cryptoxanthin alleviates myocardial ischaemia/reperfusion injury by inhibiting NF-κB-mediated inflammatory signalling in rats.

The present study aimed to explore the function and molecular mechanism of ß-cryptoxanthin on myocardial ischaemia-reperfusion injury (MIRI). Left anterior descending coronary artery ligation with reperfusion was utilised to establish a MIRI rat model. The results indicated that ß-cryptoxanthin decreases infarct size and ameliorates signs of pathological histology in MIRI. TNF-α, IL-1ß, and IL-6 levels in the serum were attenuated in response to ß-cryptoxanthin treatment, serum LDH and CK-MB activities were also decreased. Immunohistochemical analysis and western blot results suggested that p65 was translocated to the nucleus in the I/R injury rat model. However, in the ß-cryptoxanthin administration group, p65 expression and activity in the nucleus were decreased in a dose-dependent manner. Furthermore, p-p38 MAPK levels in response to ß-cryptoxanthin were decreased, indicating that MAPK is involved in NF-κB signalling pathway regulation. In conclusion, ß-cryptoxanthin alleviates myocardial ischaemia/reperfusion injury by inhibiting NF-κB-mediated inflammatory signalling in rats.

MBD2 as a Potential Novel Biomarker for Identifying Severe Asthma With Different Endotypes.

Background: Studies have shown that methyl-CpG binding domain protein 2 (MBD2) expression is significantly elevated in a neutrophil-dominant severe asthma mouse model. It also regulates Th17 cell differentiation. The objective of this study was to investigate the relationship between serum MBD2 levels in patients with severe asthma with different endotypes. Methods: Eligible adults with confirmed asthma (n = 63) underwent a clinical assessment, asthma control test and pulmonary function test and were classified as having mild, moderate or severe asthma. Severe asthma endotypes were defined according to the percentage of Th2 and Th17 cells in the peripheral blood and by the type of inflammation. The percentage of Th2 and Th17 cells in the peripheral blood was determined by flow cytometry. Serum MBD2, eosinophilic cationic protein and myeloperoxidase were measured by enzyme-linked immunosorbent assay. Correlations of MBD2 expression with clinical parameters were evaluated using Spearman's rank correlation analysis. Results: Serum MBD2 levels were upregulated in patients with severe asthma compared to healthy controls and patients with mild to moderate asthma. MBD2 was also significantly increased in patients with Th17 severe asthma compared to patients with type 2 severe asthma. Furthermore, MBD2 was positively correlated with MPO and Th17 cells but negatively correlated with ECP and Th2 cells in patients with severe asthma. Conclusions: These findings suggest that serum MBD2 may be a potential new biomarker for identifying severe asthma, Th17 severe asthma and the type of airway inflammation. However, these findings are still preliminary and need to be further investigated.

Neolignans and Diarylheptanoids with Anti-Inflammatory Activity from the Rhizomes of Alpinia zerumbet.

The dried leaves and rhizomes of Alpinia zerumbet have been traditionally used as food and medicine. Anti-inflammatory activity-guided phytochemical investigation into the rhizomes of A. zerumbet led to the isolation of 17 compounds including 10 neolignans (1-10, 1a, 1b, 2a, 2b, 3a, 3b, 4, and 5 are new compounds) and seven diarylheptanoids (11-17) in which 1-3 were three pairs of enantiomers. 4 was only one enantiomer and 5 was a racemic mixture. Compounds 1a, 1b, 2a, and 2b incorporated an 8',9'-dinorneolignan skeleton, which was rare in the lignan family. The planar structures of these compounds were elucidated by extensive analyses of spectroscopic data. The relative and absolute configurations were determined by the time-dependent density functional theory (TDDFT)-based electronic circular dichroism (ECD) calculation method. The 95% ethanol extract and ethyl acetate extract of A. zerumbet were found to show anti-inflammatory activity against croton oil-induced ear edema in mice with inhibition rates of 20.0 and 47.6% at a dose of 80 mg/kg, respectively. Bioassays showed that compounds 1a, 1b, 2a, 2b, and 12 moderately inhibited nitric oxide (NO) production in lipopolysaccharide (LPS)-induced RAW264.7 cells with IC50 values of 3.62, 7.63, 6.51, 5.60, and 8.33 µM, respectively.

GPX4 and vitamin E cooperatively protect hematopoietic stem and progenitor cells from lipid peroxidation and ferroptosis.

Ferroptosis, a newly defined mode of regulated cell death caused by unbalanced lipid redox metabolism, is implicated in various tissue injuries and tumorigenesis. However, the role of ferroptosis in stem cells has not yet been investigated. Glutathione peroxidase 4 (GPX4) is a critical suppressor of lipid peroxidation and ferroptosis. Here, we study the function of GPX4 and ferroptosis in hematopoietic stem and progenitor cells (HSPCs) in mice with Gpx4 deficiency in the hematopoietic system. We find that Gpx4 deletion solely in the hematopoietic system has no significant effect on the number and function of HSPCs in mice. Notably, hematopoietic stem cells (HSCs) and hematopoietic progenitor cells lacking Gpx4 accumulated lipid peroxidation and underwent ferroptosis in vitro. α-Tocopherol, the main component of vitamin E, was shown to rescue the Gpx4-deficient HSPCs from ferroptosis in vitro. When Gpx4 knockout mice were fed a vitamin E-depleted diet, a reduced number of HSPCs and impaired function of HSCs were found. Furthermore, increased levels of lipid peroxidation and cell death indicated that HSPCs undergo ferroptosis. Collectively, we demonstrate that GPX4 and vitamin E cooperatively maintain lipid redox balance and prevent ferroptosis in HSPCs.