Doxorubicin (DOX), which is widely used as chemotherapeutic drug in clinical work, can cause serious cardiotoxicity, and greatly reduce the survival rate, as well as quality of life of chemotherapy patients. Peroxisome proliferation activated receptor α (PPARα) is a kind of ligand activated receptor in the nuclear hormone receptor family that regulates multiple gene expression. Previous studies showed that PPARα possesses anti-apoptotic and cardio-protective effects. However, its role in DOX-induced cardiotoxicity is rarely reported. In this study, we were surprised to find decreased expression of PPARα in the heart of tumor-bearing mice treated by DOX, and there's no such phenomenon in tumor tissues. Next, we observed that PPARα agonist, fenofibrate (FENO), did not facilitates tumor progression, but enhanced cardiac function in tumor-bearing mice treated by DOX. Subsequently, recombinant adeno-associated virus serotype 9 (rAAV9) was used to manipulate the expression of PPARα in the heart of DOX-induced mice. Our results showed that PPARα gene delivery reduced cardiac dysfunction and mitochondria-dependent apoptosis in DOX-induced mice. Furthermore, we found that PPARα directly regulated the expression of mesenchyme homeobox 1 (MEOX1). Most importantly, cardioprotective effects of PPARα could be neutralized by knocking down MEOX1. In summary, PPARα plays a vital role in DOX-induced cardiotoxicity and is a promising treatment target.
Varicose veins and heart failure (HF) are increasingly prevalent. Although numbers of observational studies have indicated that varicose veins might contribute to the risk of HF, the causal relationship between them remains unclear due to the uncontrolled confounding factors and reverse causation bias. Therefore, this study aimed to explore the potential causal relationship between varicose veins and HF. Based on publicly released genome-wide association studies (GWAS), gene correlation was assessed using linkage disequilibrium score (LDSC) regression, and we conducted a two-sample Mendelian randomization (TSMR) analysis to infer the causal relationship. We performed the Inverse variance weighted (IVW) method as the primary analysis, and used Weighted median, MR-Egger, weighted mode, simple mode, and MR-pleiotropy residual sum and outlier (MR-PRESSO) methods to detect and correct for horizontal pleiotropy. LDSC revealed there was a positive genetic correlation between varicose veins and HF (r g = 0.1726184, Se = 0.04511803, P = .0001). The results of the IVW method indicated that genetically predicted varicose veins were associated with an increased risk of HF (odds ratio (OR) = 1.03; 95% confidence interval (CI): 1.01–1.06; P = .009). Our findings illustrated the significant causal effect of varicose veins on HF, suggesting that people with varicose veins might have a higher risk of HF. The results provided a novel and important perspective into the development mechanism of HF.
Based on the time when Weeds was written, the 1925-1924 correspondence between Lu Xun and Xu Guangping and the findings about their love, the author is of the opinion that Weeds was used as a symbol by Lu Xun to record his feelings and thoughts in his love with Xu Guangping.
Objective To study the relationship between blood lipid levels of pregnant women with glucose metabolism disorders and the perinatal outcomes. Methods Three hundred and fifty-eight pregnant women with glucose metabolism disorders were enrolled in this study, including 28 cases with diabetes mellitus (DM), 152 cases with gestational diabetes mellitus (GDM), 178 cases with gestational impaired glucose tolerance (GIGT). Beckman-CX9 automatic biochemical analyzer was used to measure serum levels of total cholesterol (TC), triglyceride (TG), high density lipoprotein cholesterol (HDL-C) and low density lipoprotein cholesterol (LDL-C). Results (1) The TG, TC, HDL-C and LDL-C levels in GDM group was (2.9 +/- 0.7), (6.7 +/- 1.9), (1.64 +/- 0.31), and (3.7 +/- 0.8) mmol/L, respectively, which were not significantly different from those in GIGT group [TG (2.7 +/- 0.7), TC (6.2 +/- 1.1), HDL-C (1.78 +/- 0.22), and LDL-C (3.8 +/- 0.9) mmol/L, respectively (P > 0.05)]. Maternal serum concentrations of TG and LDL-C were significantly increased in DM group [(3.6 +/- 0.9) and (4.8 +/- 0.6) mmol/L] compared with GIGT group [(2.7 +/- 0.7) and (3.8 +/- 0.9) mmol/L] and GDM group [(2.9 +/- 0.7) and (3.7 +/- 0.8) mmol/L] (P 0.05). The incidence of fetal distress in the GIGT group (9.8%) was lower than that in DM group (20.2%) and GDM group (21.4%, P Conclusion The blood lipid level of pregnant women with glucose metabolism disorders is one of the effective indexes to prognosticate perinatal outcomes. Reducing blood lipid level can decrease the incidence of pre-eclampsia and preterm labor significantly.
Background O6-methylguanine-DNA-methyltransferase (MGMT) is a specific DNA revising enzyme transferring alkylated groups from DNA to its cysteine residue to avoid the abnormal twisting of DNA. Therefore, it is one of the drug resistant genes targeted in the treatment of cancer. This study explored the protective effect of MGMT gene transferred into mammalian cells. Methods Mammalian expression vector containing the MGMT gene cloned from human hepatocytes by RT-PCR was constructed and transferred into K562 cells and human peripheral blood mononuclear cells (PBMCs) via liposome, then assayed for gene expression at RNA and protein levels. MTT assay was used to check the drug resistance of cells transfected with MGMT gene. Results MGMT gene was successfully cloned. Real-time PCR showed that the mRNA expression in gene transfected groups in K562 cell line and PBMC were 13.4 and 4.0 times that of the empty vector transfected groups respectively. Results of Western blotting showed distinct higher expression of MGMT in gene transfected group than in other two groups. The IC50 values increased to 7 and 2 times that of the original values respectively in stable transfected K562 cells and transient transfected PBMC. Conclusion The alkylating resistance of eukaryotic cells is enhanced after being transfected with MGMT gene which protein product performs the protective function, and may provide the reference for the protective model of peripheral blood cells in cancer chemotherapy.
O(6)-methylguanine-DNA-methyltransferase (MGMT) is a specific DNA revising enzyme transferring alkylated groups from DNA to its cysteine residue to avoid the abnormal twisting of DNA. Therefore, it is one of the drug resistant genes targeted in the treatment of cancer. This study explored the protective effect of MGMT gene transferred into mammalian cells.Mammalian expression vector containing the MGMT gene cloned from human hepatocytes by RT-PCR was constructed and transferred into K562 cells and human peripheral blood mononuclear cells (PBMCs) via liposome, then assayed for gene expression at RNA and protein levels. MTT assay was used to check the drug resistance of cells transfected with MGMT gene.MGMT gene was successfully cloned. Real-time PCR showed that the mRNA expression in gene transfected groups in K562 cell line and PBMC were 13.4 and 4.0 times that of the empty vector transfected groups respectively.of Western blotting showed distinct higher expression of MGMT in gene transfected group than in other two groups. The IC(50) values increased to 7 and 2 times that of the original values respectively in stable transfected K562 cells and transient transfected PBMC.The alkylating resistance of eukaryotic cells is enhanced after being transfected with MGMT gene which protein product performs the protective function, and may provide the reference for the protective model of peripheral blood cells in cancer chemotherapy.
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