OBJECTIVES: To investigate the role of METTL3 and FOXO3 in anthracycline resistance in acute myeloid leukemia (AML) cells. METHODS: Methylated RNA immunoprecipitation sequencing (MeRIP-seq) and transcriptome sequencing (RNA-seq) were performed in anthracycline-resistant and sensitive HL60 and K562 cells with lentivirus-mediated knockdown or overexpression of METTL3 and FOXO3. TCGA and GSE6891 datasets were used for analysis of the clinical and gene expression data of AMI patients. FOXO3 expressions at the mRNA and protein levels in the transfected cells were detected with RT-qPCR and Western blotting, and the changes in cell proliferation and apoptosis were evaluated using CCK8 assay and flow cytometry; the expression of m⁶A-modified mRNA and mRNA stability of FOXO3 was detected analyzed using MeRIP-qPCR and RT-qPCR. Functional enrichment analysis of the differential genes in the transfected cells was performed. RESULTS: Differential gene analysis in anthracycline-resistant versus sensitive AML cells and in cells with METTL3 knockdown revealed the enrichment in FoxO and autophagy pathways (P<0.05), and the anthracycline-resistant cells showed significantly increased m⁶A modification of FOXO3. FOXO3 expression was positively correlated with METTL3 expression. METTL3 knockdown significantly reduced FOXO3 mRNA stability and its protein levels in anthracycline-resistant AML cells, which exhibited higher m6A-modified FOXO3 expression levels than their sensitive counterparts. Database analysis, Kaplan-Meier analysis and RT-qPCR results suggested that a high FOXO3 expression was associated with a poor prognosis of AML patients. In anthracycline-resistant AML cells expressing higher FOXO3 levels than the sensitive cells, lentivirus-mediated overexpression of FOXO3 significantly enhanced cell proliferation and suppressed cell apoptosis. Inhibiting autophagy using an autophagy inhibitor (Baf.A1) obviously enhanced the inhibitory effect of adriamycin on resistant AMI cells and cells overexpressing FOXO3. CONCLUSIONS METTL3 promotes FOXO3 expression via m6A modification, and FOXO3-driven autophagy contributes to anthracycline resistance in AML cells by enhancing cell proliferation and suppressing cell apoptosis.
Humans ; Forkhead Box Protein O3/genetics* ; Leukemia, Myeloid, Acute/genetics* ; Drug Resistance, Neoplasm ; Methyltransferases/genetics* ; Autophagy ; Anthracyclines/pharmacology* ; HL-60 Cells ; Apoptosis ; Cell Proliferation ; K562 Cells

OBJECTIVES: To explore the therapeutic mechanism of compound Centella asiatica formula (CCA) for alleviating Schistosoma japonicum (Sj)-induced liver fibrosis in mice. METHODS: The active components and targets of CCA were identified using the TCMSP database with cross-analysis of Sj-related liver fibrosis targets. A "drug-component-target-pathway-disease" network was constructed using Cytoscape 3.9.1. Functional enrichment analysis (GO/KEGG) was performed using DAVID. Molecular docking study was carried out to validate interactions between the core targets and the key compounds. For experimental validation of the results, 36 mice were divided into control group, Sj-infected model group, and CCA-treated groups. In the latter two groups, liver fibrosis was induced via abdominal infection with Sj cercariae for 8 weeks, followed by 8 weeks of daily treatment with CCA decoction or saline. Hepatic pathology of the mice was assessedwith HE and Masson staining, and hepatic expressions of collagen-I and collagen-III were detected using immunohistochemistry; serum IL-6 and TNF-α levels were determined with ELISA. Hepatic expressions of TLR4 and MyD88 proteins were analyzed with Western blotting. RESULTS: We identified a total of 107 bioactive CCA components and 791 targets, including 37 intersection targets linked to Sj-induced fibrosis. The core targets included TNF, TP53, JUN, MMP9, and CXCL8, involving the IL-17 signaling, lipid metabolism, TLR4/MyD88 axis, and cancer pathways. Molecular docking study confirmed strong binding affinity between quercetin (a primary CCA component) and TNF/TP53/JUN/MMP9. In Sj-infected mouse models, CCA treatment significantly attenuated hepatic inflammatory cell infiltration, reduced collagen-I and collagen-III deposition, improved tissue architecture, reduced serum IL-6 and TNF-α levels, and downregulated TLR4 and MyD88 expressions in the liver. CONCLUSIONS CCA mitigates Sj-induced liver fibrosis by targeting TNF, TP53, JUN, and MMP9 to modulate the TLR4/MyD88 pathway, thereby suppressing pro-inflammatory cytokine release, inhibiting hepatic stellate cell activation, reducing collagen deposition, and preventing granuloma formation in the liver.
Animals ; Toll-Like Receptor 4/metabolism* ; Mice ; Myeloid Differentiation Factor 88/metabolism* ; Schistosoma japonicum ; Liver Cirrhosis/parasitology* ; Schistosomiasis japonica ; Signal Transduction ; Molecular Docking Simulation ; Inflammation ; Centella/chemistry* ; Drugs, Chinese Herbal/pharmacology* ; Tumor Necrosis Factor-alpha/metabolism*

Induced sputum testing is a non-invasive test that reflects the nature and extent of airway inflammation and plays an important role in the diagnosis, treatment and prognosis of chronic airway diseases. This article outlines the development history of induced sputum technology, introduces the principle and operation of induced sputum technology, evaluates its safety, summarizes the three main test components, elaborates the role of this technology in various chronic airway diseases, such as reflecting the type of airway inflammation, predicting the efficacy of medication, and combining it with transcriptomics to study disease mechanisms, and briefly summarizes its innovations and makes a vision for the future.

Objective To explore the mechanism of miR-421 affecting the occurrence and development of depression.Methods A depressive rat model was established by single intraperitoneal injection of lipopolysaccharide(LPS),and depressive behavior was detected by glucose preference test and open-field test.miRNA microarray chips and RT-PCR were used to analyze the expression level of miR-421 in hippocampus of the depressed rats.TargetScan database and mi RDB database were used to predict the target genes of miR-421.Dual luciferase reporter gene assay was used to observe the binding of miR-421 to the target genes.The impact of over-expression and inhibition of miR-421 on target genes was observed,then the influence of over-expression and inhibition of target genes on downstream factors was observed,and the related mechanism of miR-421 on depression was explored.Results miRNA microarray chips and RT-PCR assay showed that miR-421 was highly expressed in the hippocampus of the depressed rats(P<0.001),Inhibition of miR-421 expression could significantly restore the body weight and exercise ability of the depressed rats(P<0.001).Binding targets of Menin and miR-421 were predicted by TargetScan database,and interaction between Menin and miR-421 was demonstrated by dual-luciferase reporter gene assay.Menin expression was down-regulated while miR-421 was overexpressed(P<0.001),whereas it was up-regulated as miR-421 was inhibited(P<0.001).qPCR indicated that expressions of Caspase-3 and NF-κB in the hippocampus of the depressed rats was significantly increased(P<0.001),and IL-1β expression in the hippo-campus was significantly increased(P<0.01).When the expression of Menin was inhibited,the expressions of Caspase-3,NF-κB and IL-1β were increased(P<0.001),while the expressions of Caspase-3,NF-κB and IL-1β were decreased when Menin was overexpressed(P<0.001).Conclusions Inhibition of miR-421 expression can increase Menin expression,decrease Caspase-3 content,and reduce neuroinflammatory response,thereby improving depressive symptoms.

Mitochondrial diabetes mellitus(MDM)is a type of diabetes caused by mitochondrial gene mutations resulting in progressive secretory function defects of pancreatic islet β cells.MDM is a rare single-gene genetic disease,accounting for about 1%of all diabetes mellitus.We reported a case of MDM patient and their family.

Objective:To investigate the effects of bunched cognitive behavior intervention on disease fear and psychological security in patients with glioma.Methods:A total of 92 patients with glioma who underwent surgical treatment from January 2022 to June 2023 were selected.According to the order of enrollment, all subjects were divided into research group( n=44)and control group( n=48). The patients in control group received routine medical and nursing intervention, and patients the research group adopted glioma bunched cognitive behavior intervention on the basis of routine medical and nursing intervention, including 4 intervention cycles.At enrollment, 2 weeks after intervention, and 4 weeks after intervention, all subjects were evaluated by the fear of progression questionnaire-short form (FoP-Q-SF), safety questionnaire (SQ), self-rating anxiety scale (SAS) and self-rating depression scale (SDS). All the data in this study were processed by SPSS 26.0 statistical software.The scores of FoP-Q-SF, SQ, SAS and SDS before and after intervention were compared by repeated measures ANOVA between the two groups. Results:(1)The total FoP-Q-SF score, physiological health dimension scores, and social family dimension scores of the two groups showed significant interaction effects before and after intervention ( F=254.839, 52.738, 12.237, all P<0.05). Further simple effect analysis showed that after 2 and 4 weeks of intervention, the FoP-Q-SF scores of the research group (2 weeks after intervention: 33.80±4.94, 36.48±4.04; 4 weeks after intervention: 31.25±4.55, 35.94±4.47) and social family dimensions (2 weeks after intervention: 15.32±2.56 points, 17.06±2.14; 4 weeks after intervention: 14.05±2.59, 16.96±1.99) were lower than those of the control group (all P<0.05). The physiological health dimension score of the research group was lower than that of the control group after 4 weeks of intervention (4 weeks after intervention: 17.30±2.92, 19.06±2.38) ( P<0.05). After 4 weeks of intervention, the FoP-Q-SF score, physiological health dimension score, and social family dimension score of the research group were all lower than those at 2 weeks after intervention and before intervention (all P<0.05). (2)The total SQ score, interpersonal security dimension score and the determined control score of the two groups showed significant interaction effects before and after intervention( F=193.129, 54.706, 44.015, all P<0.05). Further simple effect testing showed that after 2 and 4 weeks of intervention, the total SQ score and interpersonal security score of the research group were higher than those of the control group (all P<0.05). The determined control score of the research group was higher than that of the control group after 4 weeks of intervention ( P<0.05). After 2 and 4 weeks of intervention, the total SQ score, interpersonal security score, and determination control score of the research group were higher than before intervention (all P<0.05), and the total SQ score and interpersonal security score of the research group were higher than 2 weeks after intervention (both P<0.05). (3)The SAS score and SDS score of the two groups showed significant interaction effects before and after intervention( F=237.867, 282.882, both P<0.05). Further simple effect analysis showed that after 2 and 4 weeks intervention, the SAS and SDS scores of the research group were lower than those of the control group (all P<0.05). The SAS and SDS scores of the research group were lower after 2 weeks and 4 weeks intervention than before intervention (all P<0.05). The SAS and SDS scores of the research group at 4 weeks after intervention were lower than those at 2 weeks after intervention (both P<0.05). Conclusion:Bundled cognitive behavioral intervention can improve disease fear and negative emotions in patients with glioma, and enhance psychological security.

Following the principles of evidence-based medicine,in accordance with the structure and drafting rules of standardized documents,based on literature research,according to the characteristics of chronic cough in children and issues that need to form a consensus,the TCM Guidelines for Diagnosis and Treatment of Chronic Cough in Children was formulated based on the Delphi method,expert discussion meetings,and public solicitation of opinions.The guideline includes scope of application,terms and definitions,eti-ology and diagnosis,auxiliary examination,treatment,prevention and care.The aim is to clarify the optimal treatment plan of Chinese medicine in the diagnosis and treatment of this disease,and to provide guidance for improving the clinical diagnosis and treatment of chronic cough in children with Chinese medicine.

Background::A phase II trial on recombinant human tenecteplase tissue-type plasminogen activator (rhTNK-tPA) has previously shown its preliminary efficacy in ST elevation myocardial infarction (STEMI) patients. This study was designed as a pivotal postmarketing trial to compare its efficacy and safety with rrecombinant human tissue-type plasminogen activator alteplase (rt-PA) in Chinese patients with STEMI.Methods::In this multicenter, randomized, open-label, non-inferiority trial, patients with acute STEMI were randomly assigned (1:1) to receive an intravenous bolus of 16 mg rhTNK-tPA or an intravenous bolus of 8 mg rt-PA followed by an infusion of 42 mg in 90 min. The primary endpoint was recanalization defined by thrombolysis in myocardial infarction (TIMI) flow grade 2 or 3. The secondary endpoint was clinically justified recanalization. Other endpoints included 30-day major adverse cardiovascular and cerebrovascular events (MACCEs) and safety endpoints.Results::From July 2016 to September 2019, 767 eligible patients were randomly assigned to receive rhTNK-tPA ( n = 384) or rt-PA ( n = 383). Among them, 369 patients had coronary angiography data on TIMI flow, and 711 patients had data on clinically justified recanalization. Both used a –15% difference as the non-inferiority efficacy margin. In comparison to rt-PA, both the proportion of patients with TIMI grade 2 or 3 flow (78.3% [148/189] vs. 81.7% [147/180]; differences: –3.4%; 95% confidence interval [CI]: –11.5%, 4.8%) and clinically justified recanalization (85.4% [305/357] vs. 85.9% [304/354]; difference: –0.5%; 95% CI: –5.6%, 4.7%) in the rhTNK-tPA group were non-inferior. The occurrence of 30-day MACCEs (10.2% [39/384] vs. 11.0% [42/383]; hazard ratio: 0.96; 95% CI: 0.61, 1.50) did not differ significantly between groups. No safety outcomes significantly differed between groups. Conclusion::rhTNK-tPA was non-inferior to rt-PA in the effect of improving recanalization of the infarct-related artery, a validated surrogate of clinical outcomes, among Chinese patients with acute STEMI.Trial registration::www.ClinicalTrials.gov (No. NCT02835534).

OBJECTIVE To conduct rapid health technology assessment （HTA） of ulinastatin （UTI）， and to evaluate the efficacy， safety and cost-effectiveness of UTI in the treatment of acute pancreatitis （AP）. METHODS Retrieved from PubMed， Embase， the Cochrane Library， CNKI， Wanfang database， CBM and official websites of HTA institutions， the systematic review （SR）/meta-analysis， economic evaluation and HTA reports of UTI in the treatment of AP were collected from the inception to Apr. 2024. Two researchers independently conducted screening， quality evaluation and data extraction according to the admission and exclusion criteria， and descriptive analysis was adopted to analyze and summarize the data. RESULTS A total of 19 studies were included， involving 15 SR/meta-analysis and 4 economic studies， and no HTA report was retrieved. In the treatment of AP， UTI showed clear advantages over conventional treatment alone in terms of improving the overall effective rate， shortening the recovery time of amylase， reducing the time required to relieve abdominal pain and distension， lowering the mortality rate， and decreasing the average hospital stay. Compared to other positive drugs （carbendate mesylate， octreotide， somatostatin， etc.）， its efficacy is similar， with a favorable safety profile. As far as the current research was concerned， UTI had obvious economic advantages over other positive drugs. CONCLUSIONS UTI is safe and effective in the treatment of AP， and has economic advantages.