Teniposide-intensified hematopoietic stem cell transplantation with acute graft versus host disease prophylaxis with anti-thymocyte globulin provides good results in high-risk or refractory recurrent hematopoietic malignant diseases.

BACKGROUND: Teniposide, as a more potent inhibitor of topoisomerase II compared with etoposide, shows less damage on hematopoietic stem cells. Few data are available on teniposide in hematopoietic stem cell transplantation (HSCT) for high-risk or refractory recurrent hematopoietic malignant diseases, particularly for acute myeloid leukemia (AML). METHODS: A retrospective single arm study was conducted to confirm the feasibility of teniposide (300 mg/m2) -intensified HSCT in the treatment of high-risk or refractory recurrent hematopoietic malignant disease by analysing the outcomes of 32 patients, who received transplantation between January 2016 and December 2018. Univariate and multivariate analyses were performed to evaluate prognostic factors of the endpoints. Statistically significant factors (P<0.05) in multivariate analyses were regarded to be predictive. RESULTS: All patients achieved myeloid engraftment at a median of 13 days (range, 9-28 days), platelet engraftment at 15.5 days (range, 6-142 days), with a cumulative incidence (CI) of platelet engraftment of 93.75%±0.26%. The CI of grade II-IV acute graft versus host disease (aGVHD) was 43.75%±0.80% and that of grade III-IV aGVHD 12.50%±0.35%. The CI of chronic (c)GVHD was 74.07%±0.82% and that of extensive cGVHD 33.33%±0.87%. The CI of relapse was 35.03%±0.76%. The one-year probability of overall survival (OS) was 62.50%±0.09%, while 2-year OS was 46.90%±0.09%, and those of 1- and 2-year leukemia-free-survival (LFS) were 56.30%±0.09% and 46.90%±0.09%, respectively. Generally, the OS and LFS until the end of our follow up were 43.50%±0.09% and 34.80%±0.11%, respectively. The probability of GVHD-free and relapse-free survival (GRFS) was 24.60%±0.08%. Multivariate analysis indicated that the probability of OS was significantly lower in patients with a disease duration of more than 280 days before receiving HSCT and in those with fewer mononuclear cells. For LFS, other than the above two factors, failure to achieve complete response (CR) before HSCT was another independent risk factor. Similarly, the probability of GRFS was significantly lower in patients with longer disease duration (≥280 days) and those receiving stem cells from female donors. CONCLUSIONS: For patients with high-risk or refractory recurrent hematopoietic malignant disease, teniposide-based conditioning regimens followed by allo-HSCT can be considered as an alternative therapy with encouraging prognoses.

[Determination Method and Characteristics of Particle Size Multiplier of PM2.5 in Road Dust].

The particle size multiplier is a valuable parameter for depicting the particle size distribution characteristics of road dust and calculating road dust emissions. In order to realize the localization of the particle size multiplier, the AP-42 and TRAKER methods were used for sampling on typical and different types of roads in Baoding in March 2019. Then, the particle size multiplier of road dust PM2.5 (K2.5) was calculated using the correction formula, and the characteristics were analyzed. The results indicated:① The K2.5 obtained separately by AP-42 and TRAKER were 0.21 g·VKT-1 and 0.23 g·VKT-1 on average, which correlated well, with a high correlation coefficient of 0.6. The PM2.5 emission factors calculated using the K2.5 of the different methods were almost at the same value, indicating that TRAKER method based on a laser sensor could measure and calculate the K2.5 and could be directly used to obtain the particle size multiplier or be converted using the fitting equation. ② The characteristics of the K2.5 in Baoding were ranked as:Expressway

Synthesis and Cytotoxicity Assessment of Novel 7-O- and 14-O-Derivatives of Glaucocalyxin A.

BACKGROUND: Rabdosia japonica has been historically used in China as a popular folk medicine for the treatment of cancer, hepatitis, and gastricism. Glaucocalyxin A (GLA), an ent-kaurene diterpene isolated from Rabdosia japonica, is one of the main active ingredients showing potent inhibitory effects against several types of tumor cells. To the best of our knowledge, studies regarding the structural modification and Structure- Activity Relations (SAR) of this compound have not yet been reported. OBJECTIVE: The aim of this study was to discover more potent derivatives of GLA and investigate their SAR and cytotoxicity mechanisms. METHODS: Novel 7-O- and 14-O-derivatives of GLA were synthesized by condensation of acids or acyl chloride. The anti-tumor activities of these derivatives against various human cancer cell lines were evaluated in vitro by MTT assays. Apoptosis assays of compound 17 (7,14-diacylation product) were performed on A549 and HL-60 cells by flow cytometry and TUNNEL. The acute toxicity of this compound was tested on mice, at the dose of 300mg per kg body weight. RESULTS: Seventeen novel 7-O- and 14-O-derivatives of GLA (1-17) were synthesized. These compounds showed potent cytotoxicity against the tested cancer cell lines, and almost all of them were found to be more cytotoxic than GLA and oridonin. Of the synthesized derivatives, compound 17 presented the greatest cytotoxicity, with IC50 values of 0.26µM and 1.10µM in HL-60 and CCRF-CEM cells, respectively. Furthermore, this compound induced weak apoptosis of A549 cells but showed great potential in stimulating the apoptosis of HL- 60 cells. Acute toxicity assays indicated that compound 17 is relatively safer. CONCLUSION: The results reported herein indicate that the synthesized GLA derivatives exhibited greater cytotoxicity against leukemia cells than against other types of tumors. In particular, 7,14-diacylation product of GLA was found to be an effective anti-tumor agent. However, the cytotoxicity mechanism of this product in A549 cells is expected to be different than that in other tumor cell lines. Further research is needed to confirm this hypothesis.

EF1A1/HSC70 Cooperatively Suppress Brain Endothelial Cell Apoptosis via Regulating JNK Activity.

AIMS: In our previous study, eEF1A1 was identified to be a new target for protecting brain ischemia injury, but the mechanism remains largely unknown. In this study, we screened the downstream cellular protein molecules interacted with eEF1A1 and found mechanism of eEF1A1 in brain ischemia protection. METHODS AND RESULTS: Through co-immunoprecipitation and mass spectrometry for searching the interaction of proteins with eEF1A1 in bEnd3 cells, HSC70 was identified to be a binding protein of eEF1A1, which was further validated by Western blot and immunofluorescence. eEF1A1 or HSC70 knockdown, respectively, increased OGD-induced apoptosis of brain vascular endothelial cells, which was detected by Annexin V-FITC/PI staining. HSC70 or eEF1A1 knockdown enhances phosphorylated JNK, phosphorylation of c-JUN (Ser63, Ser73), cleaved caspase-9, and cleaved caspase-3 expression, which could be rescued by JNK inhibitor. CONCLUSION: In summary, our data suggest that the presence of chaperone forms of interaction between eEF1A1 and HSC70 in brain vascular endothelial cells, eEF1A1 and HSC70 can play a protective role in the process of ischemic stroke by inhibiting the JNK signaling pathway activation.

Treatment with angiotensin-(1-9) alleviates the cardiomyopathy in streptozotocin-induced diabetic rats.

Diabetic cardiomyopathy, a disorder of the heart muscle in diabetic patients, is one of the major causes of heart failure. We hypothesized that angiotensin-(1-9) [Ang-(1-9)] attenuates cardiomyopathy in streptozotocin (STZ)-induced diabetic rats. Rats were injected with a single intraperitoneal injection of STZ (55 mg/kg body weight) to induced diabetic cardiomyopathy. 4 weeks later, diabetic rats were treated with Ang-(1-9) (200 ng/kg/min), angiotensin type 2 receptor (AT2R) blocker PD123319 (100 ng/kg/min), or Mas antagonist A779 (100 ng/kg/min) for 4 weeks. Although Ang-(1-9) treatment did not affect blood glucose and insulin levels, it significantly attenuated cardiac hypertrophy, reduced cardiac fibrosis and improved ventricular function in STZ-induced diabetic rats. Ang-(1-9) treatment suppressed cardiac NADPH oxidase activity and reduced formation of reactive oxygen species. Ang-(1-9) suppressed NFκB activation and reduced myeloperoxidase (MPO) activity and mRNA levels of TNFα and IL-1ß in hearts of diabetic rats. In addition, Ang-(1-9) treatment suppressed activity of ACE and reduced angiotensin II (Ang II) formation in hearts of diabetic rats. The beneficial effect of Ang-(1-9) was blunted by coadministration of PD123319 but not by coadministration of A779. Finally, it was found that Ang-(1-9) treatment could alleviate STZ-induced cardiomyopathy in a dose-dependent manner. In conclusions, Ang-(1-9) attenuates cardiac dysfunction in STZ-induced diabetic rats. The Ang-(1-9)/AT2R axis should be investigated as a novel target for treatment of type 1 diabetic cardiomyopathy.

Inhibitory effect of emodin on tissue inhibitor of metalloproteinases-1 (TIMP-1) expression in rat hepatic stellate cells.

Emodin inhibited expression of both transforming growth factor beta1 (TGFbeta1)- and phorbol ester (PMA)-induced tissue inhibitors of metalloproteinase-1 (TIMP-1) in an immortalized rat hepatic stellate cell line, HSC-T6, by Western blot and reverse transcription polymerase chain reaction. Reporter gene assays showed that emodin reduced both basal and PMA-induced activated protein-1 (AP-1) promoter activities. Electrophoretic mobility shift assay revealed that emodin reduced AP-1 DNA binding activities in HSC-T6 cells. AP-1 components analysis showed that emodin also attenuated JunD mRNA expression. Furthermore, emodin markedly inhibited TGFbeta1-induced p42/p44 mitogen-activated protein kinase phosphorylation but did not alter PMA induction. We conclude that emodin effectively inhibits PMA- and TGFbeta1-stimulated TIMP-1 expression in hepatic stellate cells by suppressing the AP-1 signaling pathway and extracellular signal-regulated kinase activation, respectively. These data provide new insight into the cellular and molecular mechanisms of emodin against liver fibrosis.