DNA methyltransferase-1 in acute myeloid leukaemia: beyond the maintenance of DNA methylation

DNA methylation is considered an essential epigenetic event during leukaemogenesis and the emergence of drug resistance, which is primarily regulated by DNA methyltransferases. DNA methyltransferase-1 (DNMT1) is one of the members of DNA methyltransferases, in charge of maintaining established methylation. Recently, DNMT1 is shown to promote malignant events of cancers through the epigenetic and non-epigenetic processes. Increasing studies in solid tumours have identified DNMT1 as a therapeutic target and a regulator of therapy resistance; however, it is unclear whether DNMT1 is a critical regulator in acute myeloid leukaemia (AML) and how it works. In this review, we summarized the recent understanding of DNMT1 in normal haematopoiesis and AML and discussed the possible functions of DNMT1 in promoting the development of AML and predicting the sensitivity of hypomethylation agents to better understand the relationship between DNMT1 and AML and to look for new hope to treat AML patients.

Key messages

• The function of DNA methyltransferase-1 in acute myeloid leukaemia.
• DNA methyltransferase-1 predicts the sensitivity of drug and involves the emergence of drug resistance.

     

Prevalence and risk factors for postinfectious cough in discharged patients with coronavirus disease 2019 (COVID-19)

BackgroundCough is one of the most common symptoms of coronavirus disease 2019 (COVID-19). However, the prevalence of persistent cough in recovered patients with COVID-19 during a longer follow-up remained unknown. This study aims to investigate the prevalence, and risk factors for postinfectious cough in COVID-19 patients after discharge.MethodsWe conducted a follow-up study for 129 discharged patients with laboratory-confirmed COVID-19 in two large hospitals located in Hubei Province, China from January 2020 to December 2020. Baseline demographics, comorbidities and smoking history were extracted from the medical record. Current symptoms and severity were recorded by a uniform questionnaire. Spirometry, diffuse function and chest computed tomography (CT) were performed on part of patients who were able to return to the outpatient department at follow-up.ResultsThe median (interquartile range) follow-up time was 8.1 (7.9–8.5) months after discharge. The mean (standard deviation) age was 51.5 (14.9) years and 57 (44.2%) were male. A total of 27 (20.9%) patients had postinfectious cough (>3 weeks), 6 patients (4.7%) had persistent cough by the end of follow-up, including 3 patients with previous chronic respiratory diseases or current smoking. Other symptoms included dyspnea (6, 4.7%), sputum (4, 3.1%), fatigue (4, 3.1%), and anorexia (4, 3.1%) by the end of follow-up. Thirty-six of 41 (87.8%) patients showed impaired lung function or diffuse function, and 39 of 50 (78.0%) patients showed abnormal CT imaging. Patients with postinfectious cough demonstrated more severe and more frequent cough during hospitalization (P<0.001), and more chronic respiratory diseases (P=0.01). In multivariate logistic regression analysis, digestive symptoms during hospitalization [odds ratio (OR) 2.95, 95% confidence interval (CI): 1.10–7.92] and current smoking (OR 6.95, 95% CI: 1.46–33.14) were significantly associated with postinfectious cough of COVID-19.ConclusionsA small part of patients developed postinfectious cough after recovery from COVID-19, few patients developed chronic cough in spite of a higher proportion of impaired lung function and abnormal lung CT image. Current smoking and digestive symptoms during hospitalization were risk factors for postinfectious cough in COVID-19.     

基于深度学习的超声影像诊断对终末期慢性肾病的价值

目的 探讨基于深度学习的卷积神经网络模型DenseNet121对终末期肾病的诊断价值.方法 回顾性选择2019年1月1日至9月30日期间中日友好医院诊断为终末期肾病的489张肾超声影像和对照组450张健康肾超声影像.采用深度卷积神经网络模型DenseNet121进行网络的训练和验证,把是否为终末期肾病作为参考标准.然后...     

Gut-derived lipopolysaccharide promotes alcoholic hepatosteatosis and subsequent hepatocellular carcinoma by stimulating neutrophil extracellular traps through toll-like receptor 4

Background/AimsBinge drinking leads to many disorders, including alcoholic hepatosteatosis, which is characterized by intrahepatic neutrophil infiltration and increases the risk of hepatocellular carcinoma (HCC). Molecular mechanisms may involve the migration of bacterial metabolites from the gut to the liver and the activation of neutrophil extracellular traps (NETs).MethodsSerum samples from both binge drinking and alcohol-avoiding patients were analyzed. Mouse models of chronic plus binge alcohol-induced hepatosteatosis and HCC models were used.ResultsA marker of NETs formation, lipopolysaccharide (LPS), was significantly higher in alcoholic hepatosteatosis and HCC patients and mice than in controls. Intrahepatic inflammation markers and HCC-related cytokines were decreased in mice with reduced NET formation due to neutrophil elastase (NE) deletion, and liver-related symptoms of alcohol were also alleviated in NE knockout mice. Removal of intestinal bacteria with antibiotics led to decreases in markers of NETs formation and inflammatory cytokines upon chronic alcohol consumption, and development of alcoholic hepatosteatosis and HCC was also attenuated. These functions were restored upon supplementation with the bacterial product LPS. When mice lacking toll-like receptor 4 (TLR4) received chronic alcohol feeding, intrahepatic markers of NETs formation decreased, and hepatosteatosis and HCC were alleviated.ConclusionsFormation of NETs following LPS stimulation of TLR4 upon chronic alcohol use leads to increased alcoholic steatosis and subsequent HCC.     

Drug D,a Diosgenin Derive,Inhibits L-Arginine-Induced Acute Pancreatitis through Meditating GSDMD in the Endoplasmic Reticulum via the TXNIP/HIF-1α Pathway

Acute pancreatitis (AP) is one of the most common causes of hospitalization for gastrointestinal diseases, with high morbidity and mortality. Endoplasmic reticulum stress (ERS) and Gasdermin D (GSDMD) mediate AP, but little is known about their mutual influence on AP. Diosgenin has excellent anti-inflammatory and antioxidant effects. This study investigated whether Diosgenin derivative D (Drug D) inhibits L-arginine-induced acute pancreatitis through meditating GSDMD in the endoplasmic reticulum (ER). Our studies were conducted in a mouse model of L-arginine-induced AP as well as in an in vitro model on mouse pancreatic acinar cells. The GSDMD accumulation in ER was found in this study, which caused ERS of acinar cells. GSDMD inhibitor Disulfiram (DSF) notably decreased the expression of GSDMD in ER and TXNIP/HIF-1α signaling. The molecular docking study indicated that there was a potential interaction between Drug D and GSDMD. Our results showed that Drug D significantly inhibited necrosis of acinar cells dose-dependently, and we also found that Drug D alleviated pancreatic necrosis and systemic inflammation by inhibiting the GSDMD accumulation in the ER of acinar cells via the TXNIP/HIF-1α pathway. Furthermore, the level of p-IRE1α (a marker of ERS) was also down-regulated by Drug D in a dose-dependent manner in AP. We also found that Drug D alleviated TXNIP up-regulation and oxidative stress in AP. Moreover, our results revealed that GSDMD^-/- mitigated AP by inhibiting TXNIP/HIF-1α. Therefore, Drug D, which is extracted from Dioscorea zingiberensis, may inhibit L-arginine-induced AP by meditating GSDMD in the ER by the TXNIP /HIF-1α pathway.     

Functional Fiber Reduces Mice Obesity by Regulating Intestinal Microbiota

Obesity may cause metabolic syndrome and has become a global public health problem, and dietary fibers (DF) could alleviate obesity and metabolic syndrome by regulating intestinal microbiota. We developed a functional fiber (FF) with a synthetic mixture of polysaccharides, high viscosity, water-binding capacity, swelling capacity, and fermentability. This study aimed to investigate the effect of FF on obesity and to determine its prevention of obesity by modulating the gut microbiota. Physiological, histological, and biochemical parameters, and gut microbiota composition were investigated in the following six groups: control group (Con), high-fat diet group (HFD), low-fat diet group (LFD, conversion of HFD to LFD), high-fat +8% FF group (8% FF), high-fat +12% FF group (12% FF), and high-fat +12% FF + antibiotic group (12% FF + AB). The results demonstrated that 12% FF could promote a reduction in body weight and epididymal adipocyte area, augment insulin sensitivity, and stimulate heat production from brown adipose tissue (BAT) (p < 0.05). Compared with the HFD, 12% FF could also significantly improve the intestinal morphological integrity, attenuate systemic inflammation, promote intestinal microbiota homeostasis, and stabilize the production of short-chain fatty acids (SCFAs) (p < 0.05). Consistent with the results of 12% FF, the LFD could significantly reduce the body weight and epididymal adipocyte area relative to the HFD (p < 0.05), but the LFD and HFD showed no significant difference (p > 0.05) in the level of inflammation and SCFAs. Meanwhile, 12% FF supplementation showed an increase (p < 0.05) in the abundance of the Bifidobacterium, Lactococcus, and Coprococcus genus in the intestine, which had a negative correlation with obesity and insulin resistance. Additionally, the treatment with antibiotics (12% FF + AB) could inhibit the effect of FF in the HFD. The Kyoto Encyclopedia of Genes and Genomes (KEGG) function prediction revealed that 12% FF could significantly inhibit the cyanogenic amino acid metabolic pathway and decrease the serum succinate concentration relative to the HFD group. The overall results indicate that 12% FF has the potential to reduce obesity through the beneficial regulation of the gut microbiota and metabolites.     

Association between Excessive Dietary Branched-Chain Amino Acids Intake and Hypertension Risk in Chinese Population

The dietary intake of branched-chain amino acids (BCAAs) has been reported to be associated with both elevated blood pressure (BP) and hypertension risk, while published findings were inconsistent, and the causality has never been well disclosed. We performed this prospective study aiming to find out the relationship between dietary BCAAs intake and hypertension risk in the Chinese population. A total of 8491 participants (40,285 person-years) were selected. The levels of dietary BCAAs intake were estimated using the 24-h Food Frequency Questionnaire. Associations of both BP values and hypertension risk with per standard deviation increase of BCAAs were estimated using linear and COX regression analysis, respectively. The hazard ratios and 95% confidence interval were given. Restricted cubic spline analysis (RCS) was used to estimate the nonlinearity. Both systolic and diastolic BP values at the end points of follow-up were positively associated with dietary BCAAs intake. Positive associations between BCAAs intake and hypertension risk were shown in both men and women. By performing a RCS analysis, the nonlinear relationship between BCAAs intake and hypertension was shown. As the intake levels of Ile, Leu, and Val, respectively, exceeded 2.49 g/day, 4.91 g/day, and 2.88 g/day in men (2.16 g/day, 3.84 g/day, and 2.56 g/day in women), the hypertension risk increased. Our findings could provide some concrete evidence in the primary prevention of hypertension based on dietary interventions.     

Associations of Nutritional,Environmental, and Metabolic Biomarkers with Diabetes-Related Mortality in U.S. Adults: The Third National Health and Nutrition Examination Surveys between 1988–1994 and 2016

Background: Nutritional, environmental, and metabolic status may play a role in affecting the progression and prognosis of type 2 diabetes. However, results in identifying prognostic biomarkers among diabetic patients have been inconsistent and inconclusive. We aimed to evaluate the associations of nutritional, environmental, and metabolic status with disease progression and prognosis among diabetic patients. Methods: In a nationally representative sample in the NHANES III (The Third National Health and Nutrition Examination Survey, 1988–1994), we analyzed available data on 44 biomarkers among 2113 diabetic patients aged 20 to 90 years (mean age: 58.2 years) with mortality data followed up through 2016. A panel of 44 biomarkers from blood and urine specimens available from NHANES III were included in this study and the main outcomes as well as the measures are mortalities from all-causes. We performed weighted logistic regression analyses after controlling potential confounders. To assess incremental prognostic values of promising biomarkers beyond traditional risk factors, we compared c-statistics of the adjusted models with and without biomarkers, separately. Results: In total, 1387 (65.2%) deaths were documented between 1988 and 2016. We observed an increased risk of all-cause mortality associated with higher levels of serum C-reactive protein (p for trend = 0.0004), thyroid stimulating hormone (p for trend = 0.04), lactate dehydrogenase (p for trend = 0.02), gamma glutamyl transferase (p for trend = 0.02), and plasma fibrinogen (p for trend = 0.03), and urine albumin (p for trend < 0.0001). In contrast, higher levels of serum sodium (p for trend = 0.005), alpha carotene (p for trend = 0.006), and albumin (p for trend = 0.005) were associated with a decreased risk of all-cause mortality. In addition, these significant associations were not modified by age, sex, or race. Inclusion of thyroid stimulating hormone (p = 0.03), fibrinogen (p = 0.01), and urine albumin (p < 0.0001), separately, modestly improved the discriminatory ability for predicting all-cause mortality among diabetic patients. Conclusions: Our nationwide study findings provide strong evidence that some nutritional, environmental, and metabolic biomarkers were significant predictors of all-cause mortality among diabetic patients and may have potential clinical value for improving stratification of mortality risk.