Research progress of FLT3 inhibitors and drug resistance mechanisms in acute myeloid leukemia / 中国临床药理学与治疗学

The FMS-like tyrosine kinase 3 (FLT3) gene mutation is the most common genetic mutation in acute myeloid leukemia (AML) and is associated with poor prognosis. Various targeted inhibitors have been developed for FLT3 mutations and have shown promising clinical efficacy. However, the emergence of resistance poses new challenges for targeted therapy in AML. This article provides an overview of the pathological and prognostic role of FLT3 mutations in AML, the current research progress on commonly used FLT3 inhibitors (type I and type II), the mechanisms of FLT3 inhibitor resistance, and strategies for overcoming resistance.

Pharmacokinetic study of five ingredients from Chitong xiaoyanling granules in rats / 中国药房

OBJECTIVE To study the pharmacokinetics of paeoniflorin， hesperidin， naringenin， formononetin and enoxolone from Chitong xiaoyanling granules in rats. METHODS Six male SD rats fasted but not deprived of water for 12 h were given Chitong xiaoyanling granules （5.0 g/kg） intragastrically at one time. Blood was collected from inner canthus of rats at different time points after administration. Plasma samples were pretreated with acetonitrile precipitated protein （sulfamethoxazole as internal standard）， and the concentrations of 5 ingredients in plasma were determined by liquid chromatography-tandem mass spectrometry （LC-MS/MS）. The pharmacokinetic parameters of each ingredient were calculated using DAS 3.0 software. RESULTS After intragastric administration of Chitong xiaoyanling granules， tmax and t1/2 of formononetin were the shortest among 5 ingredients （0.25 h and 0.39 h， respectively）. For naringenin and enoxolone， the tmax was shorter， but t1/2 was longer， and there was an obvious double-peak phenomenon in the drug-time curve of naringenin. Compared with the other three components， cmax and AUC of paeoniflorin and hesperidin were not directly proportional to the content of in vitro components. CONCLUSIONS Formononetin， naringin and enoxolone in Chitong xiaoyanling granules were absorbed rapidly in rats， while paeoniflorin and hesperidin were absorbed slowly.

Pre-hospital epidemiological characteristics in out-of-hospital cardiac arrest: who had shockable initial rhythms / 中华急诊医学杂志

Objective@#Victims with shock-able initial arrest rhythms (ventricular fibrillation or pulse-less ventricular tachycardia, VF/VT) have much better outcomes from out-of-hospital cardiac arrest (OHCA) than those with non-shock-able initial rhythms (pulse-less electrical activities, PEA or asystole). Prompt defibrillation is believed pivotal to terminate lethal shock-able arrest rhythms. In this study, we were to identify those pre-hospital epidemiological factors which were associated with likelihood of shock-able rhythms first recorded when out-of-hospital cardiac arrest occurred.@*Methods@#A multicenter, secondary, retrospective and observational analysis was performed on all adult non-traumatic OHCA in the Resuscitation Outcome Consortium (ROC) PRIMED study from June 2007 through November 2009. Of a total of 17 177 OHCA cases in PRIMED study, 13 421 of them were enrolled in this study when those OHCA patients with DNR order, or initial rhythms unknown, or arrest caused by obvious cause were excluded. We reported their demographics and episode characteristics for all enrolled cases. Multivariable logistic regression was employed to identify factors which were associated with likelihood of VF/VT recorded as shock-able initial rhythms.@*Results@#Among 13 421 adult non-traumatic OHCA cases with initial rhythms recorded, 3 527 (26.3%) of them had shock-able rhythms, while 9 894 (73.7%) patients were in non-shock-able rhythms. Of the OHCA with shock-able arrest rhythms, 1 850(52.5%) obtained return of spontaneous circulation (ROSC) in the field, while 912 (25.9%) survived to hospital discharge. On the other hand, 2489(25.2%) of the OHCA with non-shock-able arrest rhythms obtained ROSC in the field, while 325 (3.3%) of them survived to hospital discharge. Multivariable regression analysis revealed those factors which indicated likelihood of shock-able rhythms recorded were: age(OR: 0.991,95%CI 0.988-0.993), male gender (OR1.887,95%CI1.718-2.073), pre-hospital Emergency Medical System(EMS) response time(OR0.950,95%CI 0.931-0.970), cardiac arrest witnessed by EMS providers(OR1.709,95%CI 1.423-2.054) or bystander(OR3.199,95%CI 2.921-3.504) and those with bystanders CPR (OR1.357,95%CI 1.239-1.487),public place of cardiac arrest (OR2.705,95%CI 2.437-3.003).@*Conclusions@#Some demographics and pre-hospital characteristics were proved associated with likelihood of shock-able arrest rhythms first recorded in OHCA victims, which might help develop corresponding strategies to deliver prompt shock on initially shock-able patients and improve their outcomes.

Pre-hospital epidemiological characteristics in out-of-hospital cardiac arrest: who had shockable initial rhythms / 中华急诊医学杂志

Objective Victims with shock-able initial arrest rhythms (ventricular fibrillation or pulse-less ventricular tachycardia,VF/VT) have much better outcomes from out-of-hospital cardiac arrest (OHCA) than those with non-shock-able initial rhythms (pulse-less electrical activities,PEA or asystole).Prompt defibrillation is believed pivotal to terminate lethal shock-able arrest rhythms.In this study,we were to identify those pre-hospital epidemiological factors which were associated with likelihood of shock-able rhythms first recorded when out-of-hospital cardiac arrest occurred.Methods A multicenter,secondary,retrospective and observational analysis was performed on all adult non-traumatic OHCA in the Resuscitation Outcome Consortium (ROC) PRIMED study from June 2007 through November 2009.Of a total of 17 177 OHCA cases in PRIMED study,13 421 of them were enrolled in this study when those OHCA patients with DNR order,or initial rhythms unknown,or arrest caused by obvious cause were excluded.We reported their demographics and episode characteristics for all enrolled cases.Multivariable logistic regression was employed to identify factors which were associated with likelihood of VF/VT recorded as shock-able initial rhythms.Results Among 13 421 adult non-traumatic OHCA cases with initial rhythms recorded,3 527 (26.3％) of them had shock-able rhythms,while 9 894 (73.7％) patients were in non-shock-able rhythms.Of the OHCA with shock-able arrest rhythms,1 850(52.5％) obtained return of spontaneous circulation (ROSC) in the field,while 912 (25.9％) survived to hospital discharge.On the other hand,2489(25.2％) of the OHCA with non-shock-able arrest rhythms obtained ROSC in the field,while 325 (3.3％) of them survived to hospital discharge.Multivariable regression analysis revealed those factors which indicated likelihood of shock-able rhythms recorded were:age(OR:0.991,95％CI 0.988-0.993),male gender (OR1.887,95％CI1.718-2.073),pre-hospital Emergency Medical System(EMS) response time(OR0.950,95％CI 0.931-0.970),cardiac arrest witnessed by EMS providers(OR 1.709,95％CI 1.423-2.054) or bystander(OR3.199,95％CI 2.921-3.504) and those with bystanders CPR (OR1.357,95％CI 1.239-1.487),public place of cardiac arrest (OR2.705,95％CI 2.437-3.003).Conclusions Some demographics and pre-hospital characteristics were proved associated with likelihood of shock-able arrest rhythms first recorded in OHCA victims,which might help develop corresponding strategies to deliver prompt shock on initially shock-able patients and improve their outcomes.

Research on the inflammatory injury induced by N,N-dimethylformamide in H9c2 cardiomyocytes / 中国职业医学

OBJECTIVE: To explore the effect of N,N-dimethylformamide( DMF)-induced inflammatory injury in H9c2 cardiomyocytes and its mechanism. METHODS: H9c2 cardiomyocytes were cultured in vitro and randomly divided into 4different groups: control group,50 mmol / L-group,100 mmol / L-group,200 mmol / L-group. These 4 groups of cells were treated with different DMF concentrations( 0,50,100,200 mmol / L) for 12 hours. The cells were also divided into 6groups and treated with 200 mmol / L DMF at different time points( 0,2,4,6,8,12 h) : control group,2 h-group,4 hgroup,6 h-group,8 h-group and 12 h-group. The level of lactate dehydrogenase( LDH) was detected by colorimetry. The levels of creatine kinase( CK) and isoenzyme of creatine kinase( CK-MB) were detected by ultraviolet spectrometry. The levels of tumor necrosis factor-α( TNF-α),interleukin( IL)-1β,IL-6,and IL-8 were detected by enzyme linked immunosorbent assay. The level of reactive oxygen species( ROS) was detected by fluorescence probe. The location of nuclear factor-kappa B( NF-κB) p65 protein was detected by immunofluorescence cytochemistry( IFC) staining. RESULTS: The levels of LDH,CK and CK-MB in the 50 mmol / L-group,100 mmol / L-group and 200 mmol / L-group were higher than that of the control group( P < 0. 05) and showed a significant dose-effect( P < 0. 05). The levels of LDH,CK and CK-MB in the 6 h-group,8 h-group and 12 h-group were higher than that of the control group( P < 0. 01) and showed a significant time-effect( P < 0. 01). The levels of TNF-α,IL-1β,IL-6 and IL-8 of the 200 mmol / L-group were higher than the control group( P < 0. 05). Compared with the control group,the levels of TNF-α of the 4 h-group,12 h-group were higher( P < 0. 05),the levels of IL-1β of the 2 h-group,4 h-group,6 h-group,8 h-group and 12 h-group were higher( P < 0. 05),the levels of IL-6 of the 2 h-group and 4 h-group were higher( P < 0. 05),the level of IL-8 of the 2 h-group was higher( P < 0. 05). In addition,the levels of TNF-α,IL-1β and IL-6 reached a peak at 4 h-group and the level of IL-8 reached a peak at 2 h-group. The ROS levels of the 2 h-group,4 h-group and 6 h-group were higher than the control group( P < 0. 01),and the level of ROS reached a peak at 2 h-group. Furthermore,IFC staining showed that the fluorescence intensity of NF-κB p65 protein in nucleus of the 2h-group and 4 h-group increased after treatment with DMF,comparing with the control group. CONCLUSION: DMF leads to inflammatory injury in H9c2 cardiomyocytes. ROS and NF-κB might be involved in the process.

Study on apoptosis mechanism of H9c2 cardiomyocytes induced by N, N-dimethylformamide / 中华劳动卫生职业病杂志

Objective@#To observe the change levels of nuclear factor-kappa B (NF-κB) p65 protein in cytoplasm and nuclear, phosphorylation of inhibitor of kappa B (p-IκB) protein and cytochrome C (Cyt-c) , cleaved cysteinyl aspartate specific proteinase-3 (Cleaved caspase-3) , B-cell lymphoma/leukemia-2 (Bcl-2) in cytoplasm in the process of N, N-dimethylformamide (DMF) -induced apoptosis in H9c2 cardiomyocytes, and explore the tentative mechanism of apoptosis.@*Methods@#H9c2 cardiomyocytes were exposed to 200 mmol/L DMF. Western blotting was used to detect the protein expression levels of p65 in cytoplasm and nuclear, p-IκB after exposure for 0, 2, 4, 6, 8, 12 h, and the protein expression levels of Cyt-c, Cleaved caspase-3, Bcl-2 in cytoplasm after exposure for 0, 2, 4, 8, 12, 24 h. Immunofluorescencecytochemistry (IFC) was used to observe the location of Cyt-c after 200 mmol/L DMF exposure for different times.@*Results@#The levels of p65 in cytoplasm and nuclear and p-IκB among groups were statistically significant (F were 7.79, 33.11, 90.25, respectively, all P<0.01) . Compared with the control group, the levels of p65 in cytoplasm of 2, 4, 6 h group were significantly decreased (all P<0.01) ; the levels of p65 in nuclear of 2, 4, 6, 8 h were significantly increased (all P<0.01) ; the levels of p-IκB of 2, 4, 6 h group were significantly increased (all P<0.01) . The levels of Cyt-c, Cleaved caspase-3 and Bcl-2 among groups were statistically significant (F were 51.42, 503.68, 73.37, respectively, all P<0.01) . Compared with the control group, the levels of Cyt-c of 8, 12 h group were significantly increased (both P<0.01) ; the levels of Cleaved caspase-3 of 2, 4, 8, 12, 24 h were significantly increased (all P<0.01) ; the levels of Bcl-2 of 2, 4, 8, 12, 24 h group were significantly decreased (all P<0.01) . IFC showed that Cyt-c was released from the mitochondria to the cytoplasm gradually as the extension of the exposure time.@*Conclusion@#NF-κB signaling pathway and mitochondrial pathway are involved in the mechanism of DMF-induced apoptosis in H9c2 cardiomyocytes.

Protective effects of chronic clonorchis sinensis infestation on lungs of septic rat via M2 macrophages polarization / 中华急诊医学杂志

Objective To preliminarily investigate the protective effect of chronic clonorchis sinesis(Cs) infestation against sepsis in Sprague Dawley(SD) rats in order to explore its underlying mechanism.Methods Chronic Cs infestation model of SD rats was reproduced by intra-gastric administration with Cs ova.Twenty rats were randomly(random number) divided into normal group(n=10) and Cs group(n=10).The proportion of differentiation in M1 and M2 macrophages were detected by flow cytometry.The expressions of Arg-1(arginine-1),FIZZ 1,iNOs and TNF-αmRNA were examined by reverse transcriptase polymerase chain reaction(RT-PCR).The cecal ligation and puncture(CLP) procedure was performed to reproduce sepsis model of SD rats.Sixty rats were randomly(random number) divided into control group,SHAM group,CLP group,Mφ+CLP group,Cs-Mφ+CLP group,and Cs-CLP group.The cumulative mortalities were calculated.The pathological changes of the lung tissue in different groups were demonstrated by HE staining.The serum levels of cytokines TNF-α and IL-10 were detected by ELISA at 0,24,48 and 72 h after CLP procedure.Results Compared with M1 peritoneal macrophages differentiation in control group(91.9%),rat peritoneal macrophages were activated to M2 differentiation(95.1%) in chronic Cs infection group.RT-PCR assay showed expression of Arg-1 and FIZZ 1 mRNA were higher in M2 macrophages,and on the contrary, the expression of iNOS mRNA expression was higher in M1 macrophages.The expression of TNF-α mRNA in M1 was significantly higher than that in M2, whereas the expression of IL-10 mRNA in M2 was higher than that in M1.The cumulative mortality of septic rats 72 h after CLP procedure were much lower in both chronic Cs infestation group and M2 macrophages adoptive transfer group(CLP group 70%vs.Mφ+CLP group 50%vs.Cs-Mφ+CLP group 30%vs.Cs-CLP group 0%,P<0.05).In these two groups,the pathological damages in lung tissues were significantly improved.The serum level of TNF-α was decreased and the anti-inflammatory IL-10 level was increased significantly in these two groups with Cs compared with other groups.Conclusion M2 macrophages polarization induced by chronic Cs infestation with M2 phenotype gene and expression of anti-inflammatory cytokine gene play key role in increasing anti-inflammatory cytokines and decreasing pro-inflammatory cytokines to allerviate organ damage and ameliorating the survival rate in septic rats.