OBJECTIVE To investigate the ameliorative effect and mechanism of Euphorbia hirta L.-derived exosome-like nanovesicles（Eh-ENVs） on acetaminophen （APAP）-induced liver injury based on the nuclear factor erythroid 2 related factor 2 （Nrf2）/heme oxygenase-1 （HO-1）/NAD（P）H：quinone oxidoreductase 1 （NQO1） pathway. METHODS The safety of Eh-ENVs was evaluated by examining their effects on the viability of RAW264.7 and AML12 cells， as well as serum liver and kidney function indicators and histopathology of liver， lung， and other tissues in normal mice. A lipopolysaccharide （1 μg/mL）-induced RAW264.7 cell inflammation model was constructed to investigate the effects of 10 and 20 μg/mL Eh-ENVs on the mRNA expression of inflammatory factors and reactive oxygen species （ROS） level in model cells， and the uptake efficiency of Eh-ENVs by RAW264.7 cells was also examined. An APAP-induced liver injury mouse model was established to investigate the effects of 4 mg/kg Eh-ENVs on serum liver function indicators， liver histopathology， mRNA expression of inflammatory factors， malondialdehyde （MDA） level， superoxide dismutase （SOD） level， and mRNA and protein expressions related to the Nrf2/HO-1/NQO1 pathway in liver tissue of model mice. RESULTS In vitro results showed that Eh-ENVs had no inhibitory effect on the proliferation of RAW264.7 and AML12 cells；Eh-ENVs could be efficiently taken up by RAW264.7 cells and significantly reduced the mRNA expression of interleukin-1β （IL-1β）， tumor necrosis factor-α （TNF-α）， and ROS level in cells （ P ＜0.05）. In vivo results showed that 4 mg/kg Eh-ENVs had no obvious toxic side effects on normal mice，could significantly decrease the serum alanine transaminase （ALT） and aspartate transaminase （AST） levels in model mice （ P ＜0.05），upregulated/increased the mRNA expressions of IL-10， as well as the mRNA and protein expressions of Nrf2， HO-1， and NQO1， and SOD level in liver tissue （ P ＜0.05）， and down-regulated/decreased the mRNA expression of TNF-α， IL-1β and MDA level in liver tissue （ P ＜0.05）. CONCLUSIONS Eh-ENVs may activate the Nrf2/HO-1/NQO1 pathway to inhibit inflammatory response and alleviate oxidative stress， thereby improving APAP-induced liver injury.

OBJECTIVE To analyze the specific risks and long-term toxicities of four BCR-ABL1 tyrosine kinase inhibitors （TKIs）（imatinib， dasatinib， nilotinib， and bosutinib） in pediatric patients with hematological malignancies. METHODS Adverse drug event （ADE） reports submitted to the the United States FDA Adverse Event Reporting System （FAERS） from January 2012 to December 2024， with imatinib， dasatinib， nilotinib， and bosutinib as the primary suspect drugs， were collected. Data mining was performed using the reporting odds ratio method and proportional reporting ratio method. ADE terms were classified and summarized by system organ class （SOC） and preferred term （PT） according to the Medical Dictionary for Drug Regulatory Activities （MedDRA， version 26.0）. Meanwhile， the ADE reports were divided by age into the adult group （≥18 years） and the pediatric group （＜18 years） to compare the differences in ADE between the two groups. RESULTS A total of 1 512 pediatric ADE reports were included： 993 for imatinib， 391 for dasatinib， 112 for nilotinib， and 16 for bosutinib. Among the reported ADEs， the patients were mainly aged 12-＜18 years； the reports mainly originated from the United States， France， and Japan； and the primary indications were chronic myeloid leukemia and acute lymphoblastic leukemia. A total of 5 256 ADE signals were mined， among which 235 were positive signals， involving 1 103 PT across 27 SOC. The top five PT ranked by the number of positive signals were nausea， febrile neutropenia， abdominal pain， neutropenia， and anemia. The top two SOC were general disorders and administration site conditions， and gastrointestinal disorders. Compared with the adult group， the pediatric group had relatively higher proportions of events related to infections and infestations as well as blood and lymphatic system disorders. Pediatric long-term toxicity signals primarily included growth retardation， accompanied by signals related to endocrine system abnormalities and bone metabolism abnormalities. Specific signals included imatinib-associated septic shock， dasatinib-associated chylothorax， and nilotinib-associated electrocardiographic QT interval prolongation. CONCLUSIONS When pediatric patients use BCR-ABL1 TKIs， priority monitoring of infection risk and hematologic parameters is required， along with long-term follow-up of height， endocrine， and bone metabolism parameters. Targeted screening and management of drug-specific signals should be performed to ensure the long-term safety of pediatric medication.

OBJECTIVE To investigate the improvement mechanism of hyperoside （HYP） on non-alcoholic fatty liver disease （NAFLD）. METHODS Male C57BL/6 mice were randomly divided into normal （NFD） group， model （HFD） group and HYP group， with 8 mice in each group. Except for NFD group， the mice in other groups were fed with HF60 high-fat diet to establish NAFLD model； HYP group was simultaneously given HYP 100 mg/kg intragastrically every day， for 16 consecutive weeks. The body weight and liver weight of mice in each group were recorded 16 h after the last medication； the histopathological changes and lipid accumulation in the liver were observed， and the contents of triglyceride （TAG） in liver tissue and serum contents of TAG， aspartate transaminase （AST） and alanine transaminase （ALT） were measured； LC-MS/MS method was adopted to detect lipid changes in the liver tissue of mice for lipidomics analysis， and protein expressions of lipid synthesis-associated proteins peroxisome proliferator-activated receptor α （PPARα） were also tested. Human hepatocellular carcinoma cell line HepG2 was divided into normal control group， model group， HYP low-concentration group （50 μmol/L）， HYP high-concentration group （100 μmol/L）， HYP low-concentration+GW6471 （PPARαinhibitor） group， and HYP high-concentration+GW6471 group. Except for normal control group， the remaining cells were induced with oleic acid and palmitic acid to establish a high-fat cell model. The accumulation of lipid droplets in each group of cells was observed， and the TAG content was detected. RESULTS Compared with HFD group， HYP group exhibited significant reductions in liver fat vacuoles， lipid accumulation， liver weight， and TAG content in liver tissue， as well as serum contents of ALT， AST and TAG （P＜0.05）. Additionally， the expression of PPARα protein in liver tissue was significantly increased （P＜0.05）， and the pathological morphological changes associated with NAFLD were alleviated. Lipidomic analysis revealed that HYP significantly reduced the levels of TAG， diacylglycerol and other lipids in the liver. Compared with model group， cellular lipid droplet accumulation and TAG content decreased significantly in HYP low- and high-concentration groups （P＜0.05）； GW6471 could significantly reverse the improvement effect of HYP on above indicators （P＜0.05）. CONCLUSIONS HYP can effectively ameliorate NAFLD induced by a high-fat diet in mice， and the mechanism may be related to the activation of PPARα to regulate hepatic lipid synthesis.

OBJECTIVE To evaluate the contents of characteristic components in Hugan qingzhi formula(HGQZ)decoction and formulated granules and the pharmacodynamic consistency of them on high-fat diet-induced non-alcoholic fatty liver disease(NAFLD)model mice,and explore their potential underlying mechanisms of action.METHODS Liquid chromatography-tandem mass spectrometry was used to analyze and compare the contents of six characteristic components in HGQZ decoction and formulated granules.Male C57BL/6 mice were randomly divided into normal control group,model group,HGQZ decoction low-dose and high-dose groups(13,26 g/kg,calculated by crude drugs),and HGQZ formulated granules low-dose and high-dose groups(13,26 g/kg,calculated by crude drugs),with 6 mice in each group.Except for the normal control group,which was fed a regular diet,the mice in the other groups were fed a high-fat diet for 20 weeks to establish the NAFLD model;at the same time,the mice in each group were gavaged with the corresponding drugs/water once.The fasting blood glucose(FBG)levels,glucose and insulin tolerance,body weight,liver index,white adipose tissue index,brown adipose tissue index,as well as lipid levels(total cholesterol,triglycerides)and liver function indicators(aspartate transaminase,alanine transaminase)were measured.Additionally,histopathological changes and lipid accumulation in liver tissues were observed.The serum samples of mice in the model group,HGQZ decoction high-dose group and HGQZ formulated granules high-dose group were taken for metabolomics analysis,and validation of the underlying mechanisms was conducted.RESULTS There were no statistically significant differences in the contents of ginsenoside Rb1,typhaneoside,isorhamnetin-3-O-neohesperidoside,hyperoside,nuciferine,and 23-acetylalismol B between HGQZ decoction and HGQZ formulated granules(P＞0.05).Compared with the model group,the hepatic histopathological changes in mice were alleviated in both the HGQZ decoction group and all dose groups of HGQZ formulated granules.Inflammatory cell infiltration and lipid vacuoles were reduced.Additionally,there was a general improvement in FBG levels,glucose tolerance,insulin tolerance,body weight,liver index,white/brown adipose tissue index,lipid levels,and liver function indicators(P＜0.05).However,no statistically significant differences were observed between these treatment groups(P＞0.05).There were 234 and 136 differentially expressed serum metabolites identified in the model group versus HGQZ decoction high-dose group,and model group versus HGQZ formulated granules high-dose group,respectively.After taking the intersection,65 common differentially expressed metabolites were obtained,which were enriched in metabolic pathways such as purine metabolism and tricarboxylic acid cycle metabolism.Among these,the content of citrate in the model group was significantly lower than that in both the HGQZ decoction group and HGQZ formulated granules high-dose group(P＜0.05).Both high-dose HGQZ decoction and formulated granules could significantly elevate the phosphorylation levels of AMP-activated protein kinase(AMPK)(P＜0.05).CONCLUSIONS HGQZ decoction and formulated granules contain comparable amounts of characteristic components,and both exhibit equivalent efficacy on NAFLD model mice.The anti-NAFLD effects of HGQZ are associated with the activation of the AMPK energy metabolism pathway.

OBJECTIVE To study the effects of bergapten in the treatment of liver fibrosis and its mechanism based on serum metabolomics. METHODS Forty mice were divided into normal control group （0.5% carboxymethyl cellulose sodium solution）， model group （0.5% carboxymethyl cellulose sodium solution）， and BP low-dose and high-dose groups （50， 100 mg/kg）， with 10 mice in each group. Except for the normal control group， the other three groups were all treated with carbon tetrachloride to induce liver fibrosis model； they were given relevant medicine/solution intragastrically， once a day， for consecutive 8 weeks. After the last medication， the levels of alanine aminotransferase （ALT） and aspartate aminotransferase （AST） in serum were detected， and liver pathological changes were observed； the expressions of α-smooth muscle actin （α-SMA） and Collagen Ⅰ were detected in liver tissue； the serum of the mice was collected for metabolomics analysis. RESULTS Compared with the model group， serum levels of ALT and AST and protein expressions of α-SMA and Collagen Ⅰ in liver tissue were decreased significantly in BP high-dose and low-dose groups （P＜0.05）， while liver fibrosis was improved significantly. Meanwhile， metabolomics analyses showed that there were a total of 175 serum differential metabolites in the BP high-dose group and model group， of which 18 substances were upregulated and 157 substances were downregulated； the main metabolic pathways involved in bergapten intervention were pyrimidine metabolism， butanoate metabolism， fatty acid synthesis， tyrosine metabolism， β-alanine metabolism， nicotinic acid and nicotinamide metabolism， glutathione metabolism， etc. CONCLUSIONS BP is effective in the treatment of liver fibrosis by regulating pyrimidine metabolism， butanoate metabolism， glutathione metabolism and so on in rats with liver fibrosis.

OBJECTIVE To study the effects of isoliquiritigenin （ISL） regulating gut microbiota and repairing gut barrier function in model mice with non-alcoholic fatty liver disease （NAFLD）， and to clarify its mechanism for improving NAFLD. METHODS Thirty male C57BL/6J mice were randomly divided into the normal （ultrapure water）， model group （ultrapure water）， ISL group （100 mg/kg）， with 10 mice in each group. Model group and ISL group were fed with high-fat diet for 19 weeks to establish NAFLD model； at the same time， the mice were given relevant medicine/ultrapure water intragastrically. The changes of body weight in mice were recorded， and liver index， white fat index and brown fat index were calculated. The pathological changes of liver tissue and colon tissue as well as lipid accumulation were observed in mice. The levels of total cholesterol （TC）， triglyceride （TG）， aspartate aminotransferase （AST） and alanine aminotransferase （ALT） E-mail：xiangshj3@mail.sysu.edu.cn in serum or liver were measured； the serum levels of interleukin-6 （IL-6）， IL-1β and tumor necrosis factor-α （TNF-α） and the levels of IL-6， IL-1β and TNF-α mRNA expression in liver tissue were detected. Fecal samples underwent 16S rDNA sequencing analysis， and the effects of ISL on gut microbiota structure of mice were investigated. The expressions of gut mucosal barrier-related proteins （Claudin-4， Occludin and ZO-1） were determined in the colon tissue of mice. RESULTS Compared with model group， the body weight， liver index， the levels of TC in liver tissue and serum， the levels of AST and ALT in serum， the levels of IL-6， IL-1β and TNF-α in serum， and the mRNA expression of TNF-α in liver tissue were all decreased significantly in ISL group， while brown fat index was increased significantly. The inflammation and damage of liver tissue were significantly improved， and the NAFLD activity score and the proportion of lipid staining area were significantly reduced （P＜0.05）. ISL could significantly up-regulate the relative abundance of beneficial microbiota （norank_f_Muribaculaceae， Odoribacter， Ruminiclostridium， etc.） and the expressions of intestinal barrier function- related proteins， but could significantly down-regulate the relative abundance of harmful bacteria （Desulfovibrio， norank_f_Lachnospiraceae， unclassified_p_Firmicutes）， and could repair intestinal barrier. CONCLUSIONS ISL could significantly delay the progress of NAFLD， the mechanism of which may be associated with regulating gut microbiota and improving gut barrier function.

OBJECTIVE To provide reference for improving rational use of antibiotics in medical institutions. METHODS With the help of information construction， strengthening personnel training and assessment， carrying out science popularization and education， optimizing drug catalogs， equipping full-time clinical pharmacists， optimizing assessment indicators and releasing pharmaceutical information in time， new fine management mode of antibiotics was constructed in our hospital. Through the hospital information system， the relevant data of our hospital in Jan.-Dec. 2020 （before the implementation） and Jan.-Dec. 2021 （after the implementation） were collected and compared， such as utilization rate of antibiotics， intensity of antimicrobial use， the incidence of hospital infection in the inpatients， the incidence of surgical site infection， the qualified rate of antibiotic medical order， and the proportion of antibiotics in the total outbound amount of Western medicine. RESULTS Compared with 2020， the utilization rate of antibiotics in hospitalized patients in 2021 decreased from 34.94% to 32.44%， intensity of antimicrobial use decreased from 39.07 DDDs （defined daily doses） to 30.77 DDDs， and the incidence of nosocomial infections among inpatients decreased from 2.64% to 1.91%； the incidence of surgical site infections decreased from 0.26% to 0.03%； the qualified rate of antibiotic medical orders increased from 93.82% to 97.75%； the proportion of antibiotics in the total outbound amount of Western medicine decreased from 14.86% to 12.51%.CONCLUSIONS Through a series of fine management measures， our hospital has built a new fine management mode of antibiotics， which has improved the rationality of antibiotics use while ensuring the treatment effect.

OBJECTIVETo establish an in vitro cell model for investigating hepatic steatosis in non-alcoholic fatty liver disease.

METHODSL-02 cells cultured in 1640 containing 10% fetal bovine serum were divided into control group and model group. At 70%-80% confluency, L-02 cells in the model group were exposed to a long-chain mixture of free fatty acids (FFA, oleate and palmitate ) for 24 h, and cells in control group were treated with fresh medium. Lipid droplets in the cells were observed and total lipid content was determined with Oil Red O staining. The morphology of lipid droplets, trilyceride level, malonaldehyde content and cell apoptosis rate were evaluated to verify the cell model, and the effect of Huganqingzhi tablet on the lipid droplets was observed.

RESULTSA large number of lipid droplets were found in the cell model, which showed markedly increased level of triglyceride without significant changes of malonadehyde content or cell apoptosis rate. Intervention with two doses of Huganqingzhi tablet significantly decreased the number of lipid droplets and trilyceride content in the cell model.

CONCLUSIONhepatic steatosis L-02 cell model can be established by long-chain mixture of free fatty acids (oleate:spalmitate=2:1) for therapeutic drug studies.

Apoptosis ; Cell Line ; Drugs, Chinese Herbal ; pharmacology ; Fatty Acids, Nonesterified ; chemistry ; Fatty Liver ; Humans ; Malondialdehyde ; analysis ; Non-alcoholic Fatty Liver Disease ; Triglycerides ; analysis

Objective To establish an in vitro cell model for investigating hepatic steatosis in non-alcoholic fatty liver disease. Methods L-02 cells cultured in 1640 containing 10%fetal bovine serum were divided into control group and model group. At 70%-80%confluency, L-02 cells in the model group were exposed to a long-chain mixture of free fatty acids (FFA, oleate and palmitate ) for 24 h, and cells in control group were treated with fresh medium. Lipid droplets in the cells were observed and total lipid content was determined with Oil Red O staining. The morphology of lipid droplets, trilyceride level, malonaldehyde content and cell apoptosis rate were evaluated to verify the cell model, and the effect of Huganqingzhi tablet on the lipid droplets was observed. Results A large number of lipid droplets were found in the cell model, which showed markedly increased level of triglyceride without significant changes of malonadehyde content or cell apoptosis rate. Intervention with two doses of Huganqingzhi tablet significantly decreased the number of lipid droplets and trilyceride content in the cell model. Conclusion hepatic steatosis L-02 cell model can be established by long-chain mixture of free fatty acids (oleate∶spalmitate=2∶1) for therapeutic drug studies.

Objective To establish an in vitro cell model for investigating hepatic steatosis in non-alcoholic fatty liver disease. Methods L-02 cells cultured in 1640 containing 10%fetal bovine serum were divided into control group and model group. At 70%-80%confluency, L-02 cells in the model group were exposed to a long-chain mixture of free fatty acids (FFA, oleate and palmitate ) for 24 h, and cells in control group were treated with fresh medium. Lipid droplets in the cells were observed and total lipid content was determined with Oil Red O staining. The morphology of lipid droplets, trilyceride level, malonaldehyde content and cell apoptosis rate were evaluated to verify the cell model, and the effect of Huganqingzhi tablet on the lipid droplets was observed. Results A large number of lipid droplets were found in the cell model, which showed markedly increased level of triglyceride without significant changes of malonadehyde content or cell apoptosis rate. Intervention with two doses of Huganqingzhi tablet significantly decreased the number of lipid droplets and trilyceride content in the cell model. Conclusion hepatic steatosis L-02 cell model can be established by long-chain mixture of free fatty acids (oleate∶spalmitate=2∶1) for therapeutic drug studies.