Metabolic dysfunction-associated fatty liver disease （MAFLD） is a common chronic liver disease with the pathological feature of lipid accumulation in the liver， and it is closely associated with liver metabolic disorders. The latest research has shown that the pathogenesis of MAFLD is associated with the abnormal expression of specific genes， especially the fat mass and obesity-associated （FTO） gene. The abnormal activity of the FTO gene may lead to an imbalance in liver lipid metabolism， which manifests as the increase in fatty acid synthesis and the reduction in fatty acid oxidation， thereby promoting liver fat deposition and inflammatory response. Therefore， regulating the expression or activity of the FTO gene is considered one of the potential strategies for the treatment of MAFLD. At present， drug research targeting the function of the FTO gene has achieved preliminary results， and inhibition of the activity of the FTO gene can help to regulate liver lipid metabolism and alleviate liver inflammatory injury. This article reviews the mechanism of action of the FTO gene in the development and progression of MAFLD， summarizes the advances in drug research on the FTO gene and related metabolic pathways in recent years， and analyzes their application prospect in research and treatment.

OBJECTIVES: To propose a hypothesis that aloe-emodin may inhibit scar tissue fibrosis through thrombospondin-1(THBS1)-PI3K-Akt pathway. METHODS: By cultivating fibroblasts derived from scar tissue after cleft palate surgery in humans, aloe emodin of different concentrations (10, 20, 30, 40 and 50 μmol/L) was added to the cells which activity was detected. At the same time, transcriptome sequencing was performed on scar tissue and cells, and bioinformatics methods were used to explore potential targets and signaling pathways of scar tissue fibrosis. RESULTS: Aloe-emodin had a concentration dependent inhibitory effect on fibroblast proliferation,with the 40 μmol/L concentration group showing the most significant effect. The results of tissue and cell sequencing indicated that differentially expressed genes were significantly enriched in extracellular matrix-receptor interaction pathway, and shared a common differential gene which was THBS1. The ORA analysis results indicated that differentially expressed genes, including THBS1, were significantly enriched in the PI3K-Akt signaling pathway. CONCLUSIONS Aloe emodin may inhibit the PI3K-Akt pathway by downregulating THBS1, thereby reducing the proliferation activity of fibroblasts derived from postoperative palatal scar tissue.
Thrombospondin 1/genetics* ; Humans ; Signal Transduction/drug effects* ; Fibroblasts/cytology* ; Proto-Oncogene Proteins c-akt/metabolism* ; Fibrosis ; Phosphatidylinositol 3-Kinases/metabolism* ; Cicatrix/metabolism* ; Cell Proliferation/drug effects* ; Anthraquinones/pharmacology* ; Cells, Cultured

OBJECTIVE To study the chemical composition and the function of solid excipients in relieving the "nourishing and spleen-impairing" effect of Zhangbang nine steaming nine sun-dying Rehmanniae Radix(RR) by using UPLC-Q-TOF-MS technique. METHODS UPLC-Q-TOF-MS was used to collect the data of Zhangbang nine steaming nine sun-dying RR, and UNIFI platform and self-built database were used for the rapid qualitative analysis and identification of the chemical components of Zhangbang nine steaming nine sun-dying RR. The effect of solid excipients on the function of RR "nourishing and spleen-impairing" was investigated by establishing a mouse model of low gastric motility and measuring its gastric residual rate and small intestine propulsion rate. RESULTS The UPLC-Q-TOF-MS and UNFI platforms identified 76 chemical components in nine steaming nine sun-dying RR, including 9 iridoid glycosides, 11 phenylethyl glycosides, 31 flavonoids, 6 saccharides and 19 other compounds; the results of gastric emptying and small intestinal propulsion experiments on mice showed that Zhangbang nine steaming nine sun-dying RR had gastric emptying and intestinal propulsion effects. CONCLUSION This method can be used for the rapid identification and analysis of nine steaming nine sun-dying RR, which has solid excipients Citri Reticulatae Pericarpium and Amomi Fructus to alleviate the "nourishing and spleen-impairing" function of RR. This study can provide a reference for quality control and elucidation of the material basis of the medicinal effects of specialty beverage of Zhangbang nine steaming nine sun-dying RR.

Objective To investigate the effect of Porphyromonas gingivalis(Pg)infection on immune escape of oesophageal cancer cells and the role of YTHDF2 and Fas in this regulatory mechanism.Methods We examined YTHDF2 and Fas protein expressions in esophageal squamous cell carcinoma(ESCC)tissues with and without Pg infection using immunohistochemistry and in Pg-infected KYSE150 cells using Western blotting.The interaction between YTHDF2 and Fas was investigated by co-immunoprecipitation(Co-IP).Pg-infected KYSE150 cells with lentivirus-mediated YTHDF2 knockdown were examined for changes in expression levels of YTHDF2,cathepsin B(CTSB),Fas and FasL proteins,and the effect of E64(a cathepsin inhibitor)on these proteins were observed.After Pg infection and E64 treatment,KYSE150 cells were co-cultured with human peripheral blood mononuclear cells(PBMCs),and the expressions of T cell-related effector molecules were detected by flow cytometry.Results ESCC tissues and cells with Pg infection showed significantly increased YTHDF2 expression and lowered Fas expression.The results of Co-IP demonstrated a direct interaction between YTHDF2 and Fas.In Pg-infected KYSE150 cells with YTHDF2 knockdown,the expression of CTSB was significantly reduced while Fas and FasL expressions were significantly increased.E64 treatment of KYSE150 cells significantly decreased the expression of CTSB without affecting YTHDF2 expression and obviously increased Fas and FasL expressions.Flow cytometry showed that in Pg-infected KYSE150 cells co-cultured with PBMCs,the expressions of Granzyme B and Ki67 were significantly decreased while PD-1 expression was significantly enhanced.Conclusion Pg infection YTHDF2-dependently regulates the expression of Fas to facilitate immune escape of esophageal cancer and thus promoting cancer progression,suggesting the key role of YTHDF2 in regulating immune escape of esophageal cancer.

Objective To investigate the effect of Porphyromonas gingivalis(Pg)infection on immune escape of oesophageal cancer cells and the role of YTHDF2 and Fas in this regulatory mechanism.Methods We examined YTHDF2 and Fas protein expressions in esophageal squamous cell carcinoma(ESCC)tissues with and without Pg infection using immunohistochemistry and in Pg-infected KYSE150 cells using Western blotting.The interaction between YTHDF2 and Fas was investigated by co-immunoprecipitation(Co-IP).Pg-infected KYSE150 cells with lentivirus-mediated YTHDF2 knockdown were examined for changes in expression levels of YTHDF2,cathepsin B(CTSB),Fas and FasL proteins,and the effect of E64(a cathepsin inhibitor)on these proteins were observed.After Pg infection and E64 treatment,KYSE150 cells were co-cultured with human peripheral blood mononuclear cells(PBMCs),and the expressions of T cell-related effector molecules were detected by flow cytometry.Results ESCC tissues and cells with Pg infection showed significantly increased YTHDF2 expression and lowered Fas expression.The results of Co-IP demonstrated a direct interaction between YTHDF2 and Fas.In Pg-infected KYSE150 cells with YTHDF2 knockdown,the expression of CTSB was significantly reduced while Fas and FasL expressions were significantly increased.E64 treatment of KYSE150 cells significantly decreased the expression of CTSB without affecting YTHDF2 expression and obviously increased Fas and FasL expressions.Flow cytometry showed that in Pg-infected KYSE150 cells co-cultured with PBMCs,the expressions of Granzyme B and Ki67 were significantly decreased while PD-1 expression was significantly enhanced.Conclusion Pg infection YTHDF2-dependently regulates the expression of Fas to facilitate immune escape of esophageal cancer and thus promoting cancer progression,suggesting the key role of YTHDF2 in regulating immune escape of esophageal cancer.

Thirty refractory relapsed acute myeloid leukemia (R/R AML) patients who received salvage allo-HSCT with MeCBA conditioning regimen from January 2018 to June 2022 at Henan Cancer Hospital were included, and their clinical data were reviewed. There were 16 males and 14 females among the 30 patients with a median age of 37 (16-53) years. There were 3 sibling allograft donor transplants, 1 unrelated donor transplant, and 26 haplotype transplants. The median course of pre-transplant chemotherapy was 4 (3-22). The time of neutrophil engraftment was 14 (9-22) days and 18 (10-40) days for platelet. The 30-day cumulative incidence of neutrophil engraftment was 100% and the 100-day cumulative incidence of platelet engraftment was 96.7% (95% CI 85.4% -97.5% ). 22 (73.3% ) patients experienced grade 1-2 gastrointestinal reactions, and there was no grade 3-4 organ toxicity. With a median follow-up of 37.1 months, the overall survival (OS) rate, event-free survival (EFS) rate, cumulative recurrence rate (CIR), and non-recurrence mortality (NRM) rate at 3 years after transplantation were 70.0% (95% CI 50.3% -83.1% ), 65.3% (95% CI 44.8% -79.8% ), 21.2% (95% CI 9.2% -44.4% ) and 16.7% (95% CI 7.3% -35.5% ), respectively.

Periodontitis is a chronic inflammatory and immune reactive disease induced by the subgingival biofilm.The therapeutic effect for susceptible patients is often unsatisfactory due to excessive inflammatory response and oxidative stress.Sinensetin(Sin)is a nature polymethoxylated flavonoid with anti-inflammatory and antioxidant activities.Our study aimed to explore the beneficial effect of Sin on periodontitis and the specific molecular mechanisms.We found that Sin attenuated oxidative stress and inflammatory levels of periodontal ligament cells(PDLCs)under inflammatory conditions.Administered Sin to rats with ligation-induced periodontitis models exhibited a protective effect against periodontitis in vivo.By molecular docking,we identified Bach1 as a strong binding target of Sin,and this binding was further verified by cellular thermal displacement assay and immunofluorescence assays.Chromatin immunoprecipitation-quantitative polymerase chain reaction results also revealed that Sin obstructed the binding of Bach1 to the HMOX1 promoter,subsequently upregulating the expression of the key antioxidant factor HO-1.Further functional experiments with Bach1 knocked down and overexpressed verified Bach1 as a key target for Sin to exert its antioxidant effects.Additionally,we demonstrated that Sin prompted the reduction of Bach1 by potentiating the ubiquitination degradation of Bach1,thereby inducing HO-1 expression and inhibiting oxidative stress.Overall,Sin could be a promising drug candidate for the treatment of periodontitis by targeting binding to Bach1.

Objective:To assess the performance of machine learning(ML),and integrate the clinical parameters with coronary artery calcium(CAC)score of computed tomography(CT)and quantification of automated epicardial adipose tissue(EAT),so as to predict the long-term risk of myocardial infarction(MI)and cardiogenic death in asymptomatic patients.Methods:A total of 1 058 subjects with cardiovascular risk factors and without symptoms of coronary heart disease who underwent physical examination at the Fifth Medical Center of Chinese PLA General Hospital from January 2013 to October 2015 were selected as this study subjects.A long-term follow-up was conducted on them after CAC score.EAT volume and density were quantified using a fully automated deep learning method.ML extreme gradient boosting was trained by using clinical data,risk score of atherosclerotic cardiovascular disease,CAC score and automated EAT measure,and the repeated 10-fold cross validation was used to verify the model.Results:During the 8-year follow-up period,61 cases of 1 058 subjects occurred events of MI and(or)cardiac death.The area under curve(AUC)value of ML was significantly higher than that of the atherosclerotic cardiovascular disease(ASCVD)risk and the predicting events of CAC score(ML:0.82,ASCVD:0.77,CAC:0.77).Compared with ML with only clinical variable,machine learning based on ASCVD,CAC and EAT had more predictive ability for MI and cardiac death[AUC 0.82(95%CI:77-87)vs.0.78(95%CI:0.72-0.84),P=0.02].The survival rate of subjects with high ML scores had a greater decline degree with the increasing of time,therefore,the subjects with higher ML scores were more likely to experience events.Conclusion:ML,which integrated clinical and quantitative imaging variables,can provide long-term risk prediction for patients with cardiovascular risk factors.