One-carbon metabolism supports s-adenosylmethionine and m6A methylation to control the osteogenesis of BMSCs and bone formation.

The skeleton is a metabolically active organ undergoing continuous remodeling initiated by bone marrow stem cells (BMSCs). Recent research has demonstrated that BMSCs adapt the metabolic pathways to drive the osteogenic differentiation and bone formation, but the mechanism involved remains largely elusive. Here, using a comprehensive targeted metabolome and transcriptome profiling, we revealed that one-carbon metabolism was promoted following osteogenic induction of BMSCs. Methotrexate (MTX), an inhibitor of one-carbon metabolism that blocks S-adenosylmethionine (SAM) generation, led to decreased N6-methyladenosine (m6A) methylation level and inhibited osteogenic capacity. Increasing intracellular SAM generation through betaine addition rescued the suppressed m6A content and osteogenesis in MTX-treated cells. Using S-adenosylhomocysteine (SAH) to inhibit the m6A level, the osteogenic activity of BMSCs was consequently impeded. We also demonstrated that the pro-osteogenic effect of m6A methylation mediated by one-carbon metabolism could be attributed to HIF-1α and glycolysis pathway. This was supported by the findings that dimethyloxalyl glycine (DMOG) rescued the osteogenic potential in MTX-treated and SAH-treated cells by upregulating HIF-1α and key glycolytic enzymes expression. Importantly, betaine supplementation attenuated MTX-induced m6A methylation decrease and bone loss via promoting the abundance of SAM in rat. Collectively, these results revealed that one-carbon metabolite SAM was a potential promoter in BMSC osteogenesis via the augmentation of m6A methylation, and the cross talk between metabolic reprogramming, epigenetic modification, and transcriptional regulation of BMSCs might provide strategies for bone regeneration.

The bone is a self-renewing tissue that continues to reshape throughout life. Bone marrow mesenchymal stem cells (BMSCs) are essential for bone homeostasis as they are capable of osteogenic differentiation. Recent evidence suggests that BMSCs drive the osteogenic differentiation through metabolic reprogramming, but the mechanism remains unclear. In this paper, we explored the metabolic alteration following osteogenic induction of BMSCs and found that one-carbon metabolism was obviously promoted in this process. The underlining mechanisms of the osteogenic potential driven by one-carbon metabolism seem to be its contribution on N6-methyladenosine (m6A) methylation and consequent glycolysis level by providing methyl donor. We demonstrated that one-carbon metabolism-mediated m6A methylation was a potential promoter in BMSC osteogenesis, and metabolic-epigenetic coupling might provide novel therapeutic targets for bone regeneration.

The m6A eraser FTO suppresses ferroptosis via mediating ACSL4 in LPS-induced macrophage inflammation.

Acute lung injury (ALI) is a serious disorder characterized by the release of pro-inflammatory cytokines and cascade activation of macrophages. Ferroptosis, a form of iron-dependent cell death triggered by intracellular phospholipid peroxidation, has been implicated as an internal mechanism underlying ALI. In this study, we investigated the effects of m6A demethylase fat mass and obesity-associated protein (FTO) on the inhibition of macrophage ferroptosis in ALI. Using a mouse model of lipopolysaccharide (LPS)-induced ALI, we observed the induction of ferroptosis and its co-localization with the macrophage marker F4/80, suggesting that ferroptosis might be induced in macrophages. Ferroptosis was promoted during LPS-induced inflammation in macrophages in vitro, and the inflammation was counteracted by the ferroptosis inhibitor ferrostatin-1 (fer-1). Given that FTO showed lower expression levels in the lung tissue of mice with ALI and inflammatory macrophages, we further dissected the regulatory capacity of FTO in ferroptosis. The results demonstrated that FTO alleviated macrophage inflammation by inhibiting ferroptosis. Mechanistically, FTO decreased the stability of ACSL4 mRNA via YTHDF1, subsequently inhibiting ferroptosis and inflammation by interrupting polyunsaturated fatty acid consumption. Moreover, FTO downregulated the synthesis and secretion of prostaglandin E2, thereby reducing ferroptosis and inflammation. In vivo, the FTO inhibitor FB23-2 aggravated lung injury, the inflammatory response, and ferroptosis in mice with ALI; however, fer-1 therapy mitigated these effects. Overall, our findings revealed that FTO may function as an inhibitor of the inflammatory response driven by ferroptosis, emphasizing its potential as a target for ALI treatment.

Accessing 7,8-Dihydroquinoline-2,5-diones via Rh-Catalyzed Olefinic C-H Activation/[4+2] Cyclization.

Herein, we report a rhodium-catalyzed C-H activation/[4+2] cyclization reaction between α,ß-unsaturated amides and iodonium ylides for the synthesis of novel 7,8-dihydroquinoline-2,5-diones and analogues. This protocol provides a series of pyridones fused with saturated cycles with good functional group compatibility, good water and air tolerance, and good to excellent yields under mild and green reaction conditions. Additionally, scale-up synthesis can be smoothly performed with as low as 0.25 mol % catalyst loading. Recycling experiments and different transformation experiments were also carried out to demonstrate the potential synthetic utility of this protocol.

Cardiac injury in hospitalized patients with severe fever and thrombocytopenia syndrome.

Severe fever with thrombocytopenia syndrome (SFTS), an emerging infectious disease with a high fatality rate. Cardiac injury in SFTS patients is a major concern. This study aimed to evaluate the prevalence of cardiac injury and its association with mortality in hospitalized patients infected with novel Bunyavirus. Cardiac injury was defined as the presence of any of the following abnormalities: (1) blood levels of cardiac biomarkers (creatine kinase-MB, troponin-I, B-type natriuretic peptide or N-terminal pro-B-type natriuretic peptide); (2) new abnormalities in electrocardiography. The 203 SFTS patients were included in the final analysis. The proportion of SFTS patients developing cardiac injury during hospitalization was 71.4% (145/203). Compared with the uninjured group, the cardiac injury group had the severity of cardiac injury was underscored by higher median hospital costs (31420 vs. 12911, p < 0.001), higher proportion of intensive care units admissions (13.1% vs. 3.4%, p = 0.041), and higher hospital mortality rate (33.8% vs. 6.9%, p < 0.001). Multivariable-adjusted Cox proportional hazards regression analysis showed that cardiac injury was associated with higher mortality during hospitalization (hazards ratio, 7.349; 95% CI: 2.352-22.960). Cardiac injury is common among hospitalized SFTS patients, and it is associated with higher risk of mortality.

Application of free serratus anterior muscle-fascial composite tissue flap and facial lipofilling in repairing progressive hemifacial atrophy.

INTRODUCTION: Progressive hemifacial atrophy (PHA) is a nonnegligible disease, and its treatment currently lacks consensus. We aim to conduct an analysis of PHA patients to summarize the postoperative effect. Moreover, we introduced the free serratus anterior muscle-fascial composite tissue flap as a safe and novelty surgical procedure for moderate-severe PHA. METHODS: This clinical study included four patients who received a free serratus anterior muscle-fascial composite tissue flap and 19 patients who received Coleman fat transplantation. Preoperative (preoperative photograph and imageological examination) and postoperative (postoperative photograph, complications, therapeutic effect, and satisfaction) assessments were performed for all PHA patients. Body Image Concern Inventory (BICI), Self-rating Anxiety Scale (SAS), Self-rating Depression Scale (SDS) were performed preoperatively and postoperatively. RESULTS: All the cases were cured with a good appearance with two kinds of operations. Free serratus anterior muscle-fascial composite tissue flap could correct face defects in one surgery and achieve good long time and short-time postoperative satisfaction in moderate-severe PHA. Fat transplantation could also enhance appearance in numerous operations for mild-moderate PHA. The volume of free-fat grafts decreased obviously after implantation in many cases. So, many patients (42.11%) accepted a series of operations to achieve satisfied postoperative effect. BICI, SAS, SDS score decreased a year later in all patients. CONCLUSION: Free serratus anterior muscle-fascial composite tissue flap transplantation is an effective and safe treatment for moderate to severe PHA.

The Relationship Between Cord Blood Cytokine Levels and Perinatal Characteristics and Bronchopulmonary Dysplasia: A Case-Control Study.

Objective: To establish the association between serial levels of inflammatory cytokines in cord blood and perinatal characteristics and bronchopulmonary dysplasia (BPD) in preterm infants. Methods: 147 premature infants with gestational age ≤32 weeks who were born and hospitalized in the First Affiliated Hospital of Zhengzhou University between July 2019 and August 2021 were enrolled in this retrospective case-control study. Multiple microsphere flow immunofluorescence was used to detect seven cytokines in cord blood collected within 24 h of birth. Demographics, delivery characteristics, maternal factors, neonatal characteristics, and clinical outcomes were collected for the two groups. An unconditional logistic regression model was used in this study to assess the clinical variables. Results: IL-6 cord blood levels at birth were significantly higher in the BPD group than in the non-BPD group, but the odds ratio (OR) was very small (OR = 1). No differences in other cytokine concentrations were observed between the two groups. Multivariable logistic regression analysis demonstrated that increased maternal white blood cell (WBC) count on admission and lower birth weight increased the risk of BPD progression. Conclusions: Increased IL-6 cord blood levels at birth in preterm infants may have trivial significance for predicting BPD. Furthermore, higher maternal WBC count on admission and lower birth weight increased the risk of BPD.

Clinical Analysis of the Treatment of Primary Trigeminal Neuralgia by Percutaneous Balloon Compression.

PURPOSE: To summarize the technical points and clinical effects of percutaneous balloon compression (PBC) in the treatment of primary trigeminal neuralgia. METHODS: The clinical data of 13 patients with trigeminal neuralgia who received PBC from April 2020 to July 2021 were retrospectively analyzed. VAS, VRS-4 and PPI were used to evaluate the postoperative pain relief. Different postoperative complications were analyzed. RESULTS: All patients had a smooth operation, the inflation volume of the balloon was 0.7 ml, the average compression time was 120 s, and there was no balloon rupture during the operation. On the day after operation, 12 patients (92.3%) had complete pain relief, and 1 patient (7.7%) was not satisfied with pain relief, but the pain disappeared 2 weeks after the operation. After operation, there were 12 patients with facial numbness in the affected side (92.3%), 3 patients with masseter muscle weakness (23.0%), 1 patient with herpes around the mouth (7.6%), and 1 patient with diplopia (7.6%). CONCLUSION: PBC is an effective minimally invasive surgical method for the treatment of primary trigeminal neuralgia. It is suitable for the elderly and infirm people, those who cannot tolerate general anesthesia or are afraid of surgery, and patients who had undergone surgery but relapsed after surgery. However, it is necessary to pay attention to the serious facial numbness and postoperative masticatory weakness. These discomforts are generally relieved after half a year.

Three new erythrina alkaloids from the roots of Erythrina corallodendron.

Three new erythrina alkaloids, eryalkals A (1), B (2), and C (3), were isolated from the roots of Erythrina corallodendron L. Their structures, including their absolute configurations, were elucidated based on analyses of HR-ESI-MS, 1D/2D NMR and single-crystal X-ray diffraction techniques. The isolated erythrina alkaloids were screened for the antioxidant and cytotoxic activities. All the compounds showed no antioxidant activity and cytotoxic activities.

Development of a Nomogram for Moderate-to-Severe Bronchopulmonary Dysplasia or Death: Role of N-Terminal Pro-brain Natriuretic Peptide as a Biomarker.

Objectives: This study aimed to explore the clinical value of N-terminal pro-brain natriuretic peptide (NT-proBNP) in predicting moderate-to-severe bronchopulmonary dysplasia (BPD)/death, and to establish an effective clinical predictive nomogram. Methods: We retrospectively analyzed very low birth weight infants (VLBWs) with gestational age ≤ 32 weeks. The NT-proBNP values were determined on the 1st, 3rd, 7th, 14th, 21st, and 28th days after birth. The correlation between NT-proBNP level and moderate-to-severe BPD/death was evaluated. Receiver operating characteristic (ROC) curve analysis was used to evaluate the prediction ability. Then, we used multivariable logistic regression to build the prediction model and nomogram, and calibration of the model was assessed by calibration curve. Results: In total, 556 VLBWs were involved, among whom 229 developed BPD (mild: n = 109; moderate: n = 68; severe: n = 52) and 18 died. The NT-proBNP level in the moderate-to-severe BPD/death group was significantly higher than that in the no-to-mild BPD group from the 3rd to 28th day (P < 0.001). When the natural logarithm of the serum NT-ProBNP level increased by 1 unit at day 7 (±2 days) of life, the risk of moderate and severe BPD/death was the highest (OR = 3.753; 95% CI: 2.984~4.720), and ROC analysis identified an optimal cutoff point of 3360 ng/L (sensitivity: 80.0%; specificity: 86.2%; AUC: 0.861). After adjusting for confounding factors, the level of NT-proBNP at day 7 (±2 days) of life still had important predictive value for the development of moderate-to-severe BPD/death, significantly improving the predictive ability of the model. Conclusion: The level of NT-proBNP at day 7 (±2 days) of life can be used as an early promising biomarker for VLBWs to develop moderate-to-severe BPD/death. We constructed an early predictive nomogram to help clinicians identify high-risk populations.

A Good Way to Reduce Screening for Retinopathy of Prematurity: Development of the ROP Model in a China Preterm Population.

Importance: Retinopathy of prematurity (ROP) is a preventable cause of blindness in children. Without treatment, more than 45% of eyes may suffer permanent vision loss. Current ROP screening guidelines, which include a range of birth weights (BWs) and gestational ages (GAs), may require screening many low-risk preemies who might develop severe ROP. Method: All high-risk infants in the neonatal intensive care unit (NICU) of the First Affiliated Hospital of Zhengzhou University from 2017 to 2021 were included in this retrospective cohort study. Each of the 27 candidate risk factors was evaluated in univariate analysis and adjusted for known risk factors (i.e., GA and BW). The significant results were analyzed in a backward selection multivariate logistic regression model. Receiver operating characteristic (ROC) curves and a nomogram were drawn. Results: The study included 2,040 infants who underwent ROP screening. The weight gain rate [OR, 2.65; 95% confidence interval (CI), 1.49-1.21 ≤ 12 g/d vs. > 18 g/d; P = 0.001], blood transfusion (OR, 2.03; 95% CI, 1.14-3.64; P = 0.017), invasive mechanical ventilation (OR, 1.74; 95% CI, 1.15-2.66; P = 0.009) and N-terminal segment of pro-B-type natriuretic peptide (NT-proBNP) ≥ 25,000 ng/L (OR, 1.51; 95% CI, 1.00-2.28; P = 0.048) were four new statistically independent risk factors in addition to GA and BW. The area under the curve (AUC) of the final multivariate model was 0.90 (95% CI, 0.88-0.92; P < 0.001). Conclusions and Relevance: These findings add to our understanding of ROP screening because they include all eligible infants rather than only high-risk infants, as in previous studies. Under the control of BW and GA, low weight gain rate, increased number of blood transfusion, invasive mechanical ventilation and NT-proBNP ≥ 25,000 ng/L were "new" statistically independent risk factors for ROP. The ROP risk can be calculated manually or represented by a nomogram for clinical use.

Association Between NT-proBNP and Prolonged Length of Stay in Hospital Among Preterm Infants Born at 28-31 Weeks' Gestation.

OBJECTIVE: In the early life of preterm infants, the relationship between heart function and length of hospitalization is unclear. This study aims to examine the association between serum NT-proBNP level on the 7th day (NT-proBNP7) after birth and length of hospitalization among preterm infants. METHODS: A retrospective cohort study was conducted. Patients included 709 preterm infants born at 28-31 weeks' gestational age (GA) admitted to the NICU of the First Affiliated Hospital of Zhengzhou University between December 20, 2016, to April 31, 2021. Main outcome: Late discharge (postmenstrual age at discharge was in the fourth quartile (highest) among infants born at the same GA). Exposure factor: NT-proBNP7. RESULTS: We observed increased prevalence ratios for late discharge among the tertile of logarithm of NT-proBNP7 level (LnNT-proBNP7) which was positive. Compared with the lowest tertile, infants in the highest tertile of LnNT-proBNP7 had an 8.4-fold increased probability of late discharge, and the results were consistent for the subgroups. Next, a non-linear (S-shaped) relationship between LnNT-proBNP7 and late discharge was observed, whose turning points were 7.5 and 9. The effect sizes and the confidence intervals on the left of the first turning point, between two turning points and on the right of the second turning point, were 0.6 (95% CI, 0.2-1.6), 5.0 (95% CI, 2.4-10.6), and 1.1 (95% CI, 0.2-6.1), respectively. In addition, the prevalence of BPD, NEC, nosocomial infection, or any of them was highest in the group of LnNT-proBNP7 ≥ 9, lowest in the group of LnNT-proBNP7 < 7.5. CONCLUSION: Higher NT-proBNP7 levels were associated with longer hospitalization. The relationship between LnNT-proBNP7 and late discharge was S-shaped. LnNT-proBNP7 was positively related with late discharge when LnNT-proBNP7 was between 7.5 and 9.

Development and Validation of a Dynamic Nomogram to Predict the Risk of Neonatal White Matter Damage.

PURPOSE: White matter damage (WMD) was defined as the appearance of rough and uneven echo enhancement in the white matter around the ventricle. The aim of this study was to develop and validate a risk prediction model for neonatal WMD. MATERIALS AND METHODS: We collected data for 1,733 infants hospitalized at the Department of Neonatology at The First Affiliated Hospital of Zhengzhou University from 2017 to 2020. Infants were randomly assigned to training (n = 1,216) or validation (n = 517) cohorts at a ratio of 7:3. Multivariate logistic regression and least absolute shrinkage and selection operator (LASSO) regression analyses were used to establish a risk prediction model and web-based risk calculator based on the training cohort data. The predictive accuracy of the model was verified in the validation cohort. RESULTS: We identified four variables as independent risk factors for brain WMD in neonates by multivariate logistic regression and LASSO analysis, including gestational age, fetal distress, prelabor rupture of membranes, and use of corticosteroids. These were used to establish a risk prediction nomogram and web-based calculator (https://caowenjun.shinyapps.io/dynnomapp/). The C-index of the training and validation sets was 0.898 (95% confidence interval: 0.8745-0.9215) and 0.887 (95% confidence interval: 0.8478-0.9262), respectively. Decision tree analysis showed that the model was highly effective in the threshold range of 1-61%. The sensitivity and specificity of the model were 82.5 and 81.7%, respectively, and the cutoff value was 0.099. CONCLUSION: This is the first study describing the use of a nomogram and web-based calculator to predict the risk of WMD in neonates. The web-based calculator increases the applicability of the predictive model and is a convenient tool for doctors at primary hospitals and outpatient clinics, family doctors, and even parents to identify high-risk births early on and implementing appropriate interventions while avoiding excessive treatment of low-risk patients.

[Chemical compositions from roots of Erythrina corallodendron].

This project is to investigate chemical compositions from the roots of Erythrina corallodendron. Through the methods of silica gel,ODS,Sephadex LH-20 column chromatography and preparative HPLC,15 compounds were isolated from the 95% ethanol extract of the roots of E. corallodendron. Based on spectroscopic techniques,the structures of these compounds were identified as 10,11-dioxoerythraline( 1),erythrinine( 2),erythraline( 3),11-methoxyerythraline( 4),cristanines B( 5),erythratine( 6),erysotrine( 7),medioresinol( 8),( ±)-ficusesquilignan A( 9),( +)-pinoresinol( 10),nicotinic acid( 11),dibutyl phthalate( 12),vanillic acid( 13),3-hydroxy-1-( 4-hydroxy-3-methoxyphenyl)-1-propanone( 14),and syringic acid( 15). Compounds 8-10 are isolated from genus Erythrina for the first time and all compounds are isolated from E. corallodendron for the first time. Furthermore,this paper screened the antioxidant and cytotoxic activities of the compounds using models of liver microsomal oxidation inhibition and MTT.