Objective To investigate the effect of histone deacetylase inhibitor LBH589 on proliferation,apoptosis and drug resistance of chemoresistant acute myeloid leukemia cells HL60/ADM.Methods HL60/ADM cells were treated with LBH589.Proliferation,apoptosis and adriamycin IC50 were evaluated by MTT assay and AnnexinV-FITC/PI stain.The change in MRP1 expression and intercellular adriamycin accumulatiom were analyzed by flow cytometry.Results Effective proliferative inhibition and apoptotic induction in HL60/ADM cells were observed after treatment with 10-80 nmol/L LBH589 with maximal effect detected after treatment with 70 nmol/L LBH589 for 60 hours.However,inhibition ratio remain unchanged with the further increase of drug dose and incubation time (P ＞ 0.05).Downregulation of MRP1 [(93.90±4.20) ％ vs (76.19±6.53) ％],upregulation of adriamycin accumulation [(8.53±0.68) ％ vs (25.67±1.34) ％] and decrease in adriamycin IC50 [(6.833±0.319) μg/ml vs (1.382±0.104) μg/ml] were induced by the treatment with 20 nmol/L LBH589 (P ＜ 0.01),whose reversal fold was 4.9.The expression of acetylated histone 3 after treatment with LBH589 was higher than that before treatment (P ＜ 0.01).However,relative p-Akt levels after treatment for 24 h and 48 h were 1.07±0.09 and 0.59±0.01,respectively,which were lower than that before treatment (2.03±0.12) (P ＜ 0.01).Meanwhile,expression levels of p53 were 0.57±0.04 and 1.31±0.09,respectively,which were higher than that before treatment (0.21 ±0.02) (P ＜ 0.01).Conclusion Treatment with LBH589 has the capability of inhibiting proliferation and inducing apoptosis,as well as increasing intercellular adriamycin accumulation and sensitivity through downregulation of MRP1 expression and inhibition of PI3K-Akt signaling pathway in HL60/ADM cells.

Objective To study the time-toxicity and dose-toxicity relationship of hepatotoxicity induced by Paracetamol Tablets (PT),Compound Paracetamol and Amantadine Hydrochloride Tablets (CPAH),Compound Dextromethorphan Hydrobromide Tablets (CDH),and Chaiqin Qingning Capsules (CQC) with single dose in mice.Methods In the Time-Toxicity relationship study,Kunming mice were randomly divided into control,PT,CPAH,CDH,and CQC group,and mice of.each drug administration group were randomly divided into nine subgroups according to the time (1,2,4,8,12,24,48,72 and 96 h after administration) of blood collection.The acetaminophen contents in PT,CPAH,and CDH groups were 425.98 mg/kg,and the dose of CQC group was 3 680.50 mg/kg.In the Dosage-Time relationship study,mice were randomly divided into control,PT,CPAH,CDH,and CQC high,medium and low dose group.The acetaminophen contents of high,medium,and low dose were 266.24,425.98,and 681.57 mg/kg in PT,CPAH,and CDH group,and the dose of CQC group was 1437.70,2300.31,and 3680.50 mg/kg,10 mice in each group,sex in half.Blood was collected 12 h after administration.Animal behavior was observed every day,blood and organs were collected at the corresponding time points,serum alanine aminotransferase (ALT),aspartate aminotransferase (AST),and alkaline phosphatase (ALP) level were detected,and the organs index of spleen and thymus,liver were calculated.Results There were no significant changes of ALT,AST,ALP,and organs index after once ig administration of CQC at dosage of 1437.70 mg/kg to 3680.50 mg/kg in mice.The study on time-toxicity relationship indicated that,after once administration of PT,CPAH,and CDH at 425.98 mg/kg,mice showed toxic symptom such as hypokinesia,dry hair and so on,12 h was the most obvious,24 ～ 72 h disappeared.The level of ALT,AST,and ALP in serum increased and reached to the peak at 12 h and then restored near normality after 72,24,and 24 h in PT,CPAH,and CDH group.Their organ index of liver,spleen and thymus all had no significant changes.The study on the dosage-toxicity relationship indicated that,there were no significant changes of animal behavior,ALT,AST,ALP,and organs index after once ig administration of PT,CPAH,and CDH at 266.24 mg/kg.Obvious liver injury can be induced by the three drugs with dosage of 425.98 to 681.57 mg/kg and the level of ALT,AST,and ALP increased significantly with the increase of dosage.Their liver index increased significantly with dosage of 681.57 mg/kg,but the organs index of spleen,thymus had no significant changes.Conclusion There was no hepatotoxicity after once ig administration of CQC with dosage of 3680.50 mg/kg in mice.Mice were once ig administration ofPT,CPAH,and CDH with a large dose,may induce acute liver injury and show obvious time-toxicity and dose-toxicity relationships.

Objective To study the dose-time-toxicity relationship of hepatotoxicity in mice with multiple administration of Paracetamol Tablets (PT),Compound Paracetamol and Amantadine Hydrochloride Tablets (CPAH),Compound Dextromethorphan Hydrobromide Tablets (CDH),and Chaiqin Qingning capsules (CQC).Methods Mice were randomly divided into control,PT,CPAH,CDH,and CQC high,medium,and low dose groups.The acetaminophen contents of high,medium,and low doses were 266.24,425.98,and 681.57 mg/kg in PT,CPAH,and CDH groups,and the doses of CQC group were 1437.70,2300.31,and 3 680.50 mg/kg,ig administration,once daily for 5 d.General state and toxicity of mice were observed.The changes of ALT,AST,AKP,TBIL,and ALB levels in serum and organ indexes of liver,spleen,thymus,and kidney were tested on day 1,3,7,11,and 14 after multiple administration.Results CQC with the dosage range of 1 437.70-3 680.50 mg/kg to mice within 14 d,has not yet induced the increase of AST,ALT,AKP,TBIL,and ALB levels and changes of organ indexes of liver,thymus spleen,and kidney compared with normal control (P ＞ 0.05).PT,CPAH,and CDH with repeated dose of 425.98-681.57 mg/kg could induce significant increase of the levels ofALT,AST,AKP,and TBIL which reached the peak on day 1 (P ＜ 0.05),and then gradually decreased on day 3-14.The level of ALB significant decreased on day 1-11 (P ＜ 0.05),and then gradually recovered on day 11-14.The liver index significant increased on day 1-3 (P ＜ 0.05),and recovered on day 7-14.Conclusion Multiple administration of CQC could not induce liver injury in mice within 14 d,while multiple administration ofPT,CPAH,and CDH could induce hepatotocixity in mice with a certain dose,and show an obvious dose-time-toxicity relationship.

Objective:To investigate the effect of dexmedetomidine combined with chloroprocaine on epidural anesthesia for cesarean section.Methods:A total of 133 women who underwent epidural anesthesia for cesarean section at the Department of Anesthesiology, Jinhua People's Hospital between January 2020 and December 2022 were included in this prospective case-control study. These women were divided into a ropivacaine group ( n = 66) and a chloroprocaine group ( n = 67) using a random number table method. The ropivacaine group received epidural anesthesia with dexmedetomidine combined with ropivacaine, while the chloroprocaine group received epidural anesthesia with dexmedetomidine combined with chloroprocaine. The anesthesia effect (anesthesia onset time, anesthesia duration, peak effect time), changes in blood pressure (systolic blood pressure, diastolic blood pressure), adverse reactions (shivering, nausea and vomiting, urinary retention, skin itching, numbness of lower limbs), and satisfaction with muscle relaxation were observed in the two groups. Results:The anesthesia onset time, anesthesia duration, and peak effect time in the chloroprocaine group were (6.91 ± 1.54) minutes, (61.54 ± 5.31) minutes, and (11.79 ± 4.12) minutes, respectively, which were significantly shorter than those in the ropivacaine group [(9.65 ± 1.92) minutes, (83.57 ± 6.69) minutes, (18.32 ± 4.81) minutes, t = 9.08, 21.05, 8.41, all P < 0.001). The systolic and diastolic blood pressure increased in both groups after 10 minutes of anesthesia and at the end of the procedure; however, the increments observed in the chloroprocaine group were relatively smaller. There were significant differences in systolic and diastolic blood pressure, measured at 10 minutes of anesthesia and at the end of the procedure, between the two groups ( F = 7.36, P < 0.001; F = 5.12, P = 0.001). There were significant differences in systolic and diastolic blood pressure between different time points ( F = 10.03, P < 0.001; F = 6.72, P < 0.001). The group-by-time interaction effect on systolic and diastolic blood pressure was also highly significant ( F = 9.83, P < 0.001; F = 8.01, P < 0.001). The chloroprocaine group exhibited a significantly lower incidence of adverse reactions compared with the ropivacaine group [4.48% (3/67) vs. 15.15% (10/66), χ2 = 4.29, P < 0.05). Additionally, the chloroprocaine group had a significantly higher satisfaction rate with muscle relaxation compared with the ropivacaine group [94.03% (63/66) vs. 81.82% (54/66), Z = 5.73, P < 0.05]. Conclusion:The combination of dexmedetomidine and chloroprocaine offers remarkable benefits in epidural anesthesia for cesarean sections. This combined approach not only enhances epidural anesthesia but also stabilizes the blood pressure of puerperants, reduces adverse reactions, and provides exceptional muscle relaxation. It deserves consideration for clinical application.

Objective: To explore the injury pattern and features of peripheral nerve in congenital muscular dystrophy patients caused by LAMA2 gene mutation. Method: Seventeen patients genetically or molecular pathologically diagnosed as LAMA2-related congenital muscular dystrophy were recruited in Peking University First Hospital between 2002 and 2015. All the patients received nerve conduction velocity (NCV) and needle electromyography tests. Clinical and laboratory examination data of the patients was retrospectively analyzed. The correlation between the NCV and disease course was determined by Pearson correlation analysis. Additionally, one patient underwent a sural nerve biopsy. Result: Among these 17 identified patients (13 male and 4 female), all of them were diagnosed as congenital muscular dystrophy, and all of them underwent electrophysiological examination at ages between 1 month to 6 years. Electromyogram indicated seventeen patients of myogenic damage, of whom 10 cases were complicated with reduced NCV. Twenty-six of 95 analyzed nerves showed NCV slower than the normal average of contemporary in 17%-47%. Correlation analysis between NCV and the disease course indicated that NCV of median nerves, ulnar nerves, tibial nerves and common peroneal nerves were negatively associated with the disease course (r=-0.737, -0.771, -0.540 and -0.682, respectively; all P<0.05). Sural nerve biopsy revealed peripheral neuropathy changes of myelin. Conclusion There is peripheral nerve injury in LAMA2-related muscular dystrophy patients. It mainly manifests as demyelinating lesions. Moreover, the NCV of peripheral nerve will decrease with the increase of the course of the disease.