1.Research progress of PARP inhibitors in cancers and their drug resistance
Wanwan YANG ; Fangyu YE ; Yujia WU ; Haochen WANG ; Li ZHAO
Journal of China Pharmaceutical University 2022;53(5):525-534
Poly ADP-ribose polymerase-1 (PARP-1) plays a vital role in organisms, including regulating repair of DNA, maintaining genome stability, regulating cell proliferation, differentiation, and death.At present, PARP inhibitors have been made some breakthrough in the treatment of breast cancer, ovarian cancer, prostate cancer and pancreatic cancer.However, PARP inhibitors have certain limitations in other malignant tumors and patients who are resistant to PARP-1 inhibitors.This article summarizes the research on PARP inhibitors in lung cancer, hepatocellular carcinoma, glioblastoma, leukemia and cervical cancer, and introduces the strategies of combining other anti-tumor drugs such as DNA repair inhibitors, immune checkpoint inhibitors, anti-angiogenic drugs and other chemotherapeutic drugs to solve their drug resistance, which provides some reference for the wide clinical application of PARP inhibitors in the future.
2. Research progress of FLT3 inhibitors and drug resistance mechanisms in acute myeloid leukemia
Tingkai WU ; Chongchong REN ; Wanwan ZHANG ; Bei LIU
Chinese Journal of Clinical Pharmacology and Therapeutics 2024;29(1):90-98
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.
3.Establishment and application of public health risk assessment indexes for flood disaster.
Jiabing WU ; Lei GONG ; Fang CHEN ; Dandan SONG ; Wanwan MA ; Sai HOU
Journal of Zhejiang University. Medical sciences 2018;47(2):118-123
OBJECTIVETo establish a public health risk assessment indexes for flood disaster.
METHODSDelphi method and expert consultation were used to establish the public health risk assessment index system and scoring criteria, and the analytic hierarchy process (AHP) method was used to obtain the weight of the indexes. Then, the established index system was applied to evaluate the public health risk of the flood disaster in Anhui province, 2016.
RESULTSA public health risk assessment system consisting of 5 categories and 17 indexes was constructed. The assessment result of the flood disaster in Anhui province of 2016 showed that the public health risk score was 0.26, suggesting that "the health emergency measures were effective, and the public health risks were effectively controlled".
CONCLUSIONSThe established indexes can effectively assess the health risk of flood disaster and also can provide the reference for other disaster assessment.
Disasters ; Floods ; Risk Assessment
4.Effect of Linggui Zhugantang on Mitochondrial Fusion-fission and Sirt3/ AMPK Signaling Pathway in Chronic Heart Failure Rats After Myocardial Infarction
Juan YAO ; Rui DING ; Xiangyang LI ; Tongjuan TANG ; Wanwan WU ; Kedong WEI ; Shaohua XU ; Liang WANG ; Peng ZHOU ; Jinling HUANG
Chinese Journal of Experimental Traditional Medical Formulae 2024;30(3):1-9
ObjectiveTo investigate the effects of Linggui Zhugantang on mitochondrial fission and fusion and silencing information regulator 3(Sirt3)/adenosine monophosphate dependent protein kinase (AMPK) signaling pathway in chronic heart failure (CHF) rats after myocardial infarction (MI). MethodSD rats randomly divide into sham operation group (normal saline ,thread only without ligature), model group (normal saline, ligation of the left anterior descending coronary artery proximal to the heart), Linggui Zhugantang group (4.8 g·kg-1) and Captopril group (0.002 57 g·kg-1), with 10 rats in each group. Administere drug continuously for 28 days. Echocardiography detected cardiac function parameters. Hematoxylin eosin (HE) staining observed the pathological changes of the heart. Immunofluorescence detected the levels of reactive oxygen species (ROS). JC-1 detect mitochondrial membrane potential. Colorimetry measure adenosine triphosphate (ATP), superoxide dismutase (SOD), malondialdehyde (MDA), mitochondrial respiratory chain complex activity (Ⅰ-Ⅳ). TdT-mediated dUTP nick end labeling (TUNEL) staining detected the apoptosis rate of myocardial tissue. Western blot detected protein expression levels of Sirt3, phosphorylated AMPK (p-AMPK), phosphorylated dynamic-related protein 1(p-Drp1), mitochondrial fission protein 1(Fis1), mitochondrial fission factor (MFF), optic atrophy protein 1(OPA1). ResultCompared to the sham group, the left ventricular end diastolic diameter (LVIDd) and left ventricular end systolic diameter (LVIDs) were significantly increased in model group (P<0.01), while the left ventricular short axis shortening rate (LVFS) and left ventricular ejection fraction (LVEF) were significantly decreased (P<0.01). There were inflammatory cell infiltration and obvious pathological injury in myocardial tissue. ROS, MDA levels and myocardial cell apoptosis rate were significantly increased (P<0.01), SOD level, ATP content, and membrane potential were significantly decreased (P<0.01). The activity of mitochondrial respiratory chain complexes (Ⅰ-Ⅳ) was significantly decreased (P<0.01). Levels of p-Drp1, Fis1, MFF proteins were significantly up-regulated (P<0.01), while Sirt3, p-AMPK, OPA1 proteins level were significantly down-regulated (P<0.01). Compared with model group, LVIDd and LVIDs were significantly decreased (P<0.01), LVEF and LVFS were significantly increased (P<0.01). Inflammatory cell infiltration and pathological damage of myocardial tissue were significantly relieved. ROS, MDA levels and myocardial cell apoptosis rate were significantly decreased in Linggui Zhugantang group and Captopril group (P<0.01), SOD level, ATP content, and membrane potential significantly increased (P<0.01). The activity of mitochondrial respiratory chain complexes (Ⅰ-Ⅳ) increased significantly (P<0.01),and p-Drp1, Fis1, MFF protein levels were significantly down-regulated (P<0.01), Sirt3, p-AMPK, OPA1 protein were significantly up-regulated (P<0.01). ConclusionLinggui Zhugantang can alleviate oxidative stress and apoptosis damage of myocardial cells, maintain mitochondrial function stability, and its effect may be related to mitochondrial mitosis fusion and Sirt3/AMPK signaling pathway.