Jun Xu

Fibroblast activation protein-α (FAPα) is a promising tumor-associated target expressed by reactive stromal fibroblasts in tumor tissue. FAPα has a postprolyl peptidase activity and can specifically cleave N-terminal benzyloxycarbonyl (Z)-blocked peptides, such as the substrate Z-Gly-Pro-AMC. Doxorubicin (DOX) is an effective antitumor drug, but its application is greatly limited by toxic adverse effects owing to poor tumor selectivity. Based on these facts, we previously designed a FAPα-targeting prodrug of doxorubicin (FTPD) which can be selectively hydrolyzed by FAPα. FTPD can retain potent antitumor efficacy and has favorable tumor targeting. The present study aimed to further evaluate the toxicological profile and the safety pharmacological property of FTPD in vitro and in vivo. The cytotoxicity assay showed that FTPD displayed markedly lower cytotoxicity to 3T3 cells and HEK-293 cells compared with DOX. In the short-term toxicity study, mice treated with 25 mg/kg of FTPD showed no obvious change in the appearance and general behavior, and no case of mortality was observed within 14 days. Unlike DOX, FTPD exhibited reduced toxicity to heart, liver, kidney, spleen as well as peripheral white blood cells in mice. Moreover, open file test and general pharmacology study were also conducted correspondingly in mice and beagle dogs. It was found that FTPD may not produce significant pharmacological effects on spontaneous locomotor activity and cardiovascular-respiratory system except for a transient decreasing in systolic blood pressure. Taken together, the results of this work suggest that FTPD has more favorable toxicological profile and better drug safety compared with its parent drug DOX.

A hydrophobic porous MOF functionalized by methyl groups with a chemical formula {[Cd ₂ (oba) ₂ (dmbpy)(H ₂ O)]⋅2(EtOH)⋅4(H ₂ O)} _n ( 1 ) (oba=4,4′‐oxydibenzoate, dmbpy=3,3′‐dimethyl‐4,4′‐bipyridine, EtOH=ethanol) was synthesized and structurally characterized. 1 exhibits a 3D framework with a 1D channel parallel to the c axis. TGA, PXRD, and water vapor sorption results show high thermal and water stability for the framework. More importantly, 1 shows a very high adsorption selectivity to CO ₂ as compared to other small gas molecules (e. g. CH ₄ , N ₂ , O ₂ , CO and H ₂ ) at 298 K based on the results of simulations and experiments.

A hydrostable anionic porous drug carrier MOF with a bcu topology constructed from trinuclear clusters, [(Me₂NH₂)₂Zn₃(fdc)₄]_n·DMA (1) (fdc = 2,5-furandicarboxylate, DMA = dimethylacetamide), was synthesized and structurally characterized. TGA, PXRD, and water vapor sorption results show high thermal and water stability for the framework. 1 exhibits a 3D framework with rectangular channels of 10.0 × 7.7 and 6.1 × 7.8 Ų along the b axis. Desolvated 1 adsorbs around 17.2 wt% 5-fluorouracil and the cumulative release value of 5-fluorouracil at 72 h was about 93.3% in PBS (pH 7.4) at 37 °C. Results of in vivo zebrafish toxicity tests and in vitro MTT assays of 1 at different concentrations reveal that 1 is nontoxic.

In this study, a systematic evaluation was conducted to estimate the efficacy and safety of ticagrelor for treating acute coronary syndrome (ACS) in general ACS patients and a diabetes mellitus (DM) group. A search of PubMed, Cochrane Central Register of Controlled Trials, Web of Science, CNKI databases was conducted to analyze relevant randomized controlled trails (RCTs) of ticagrelor treating ACS during 2007 to 2015. Article screening, quality accessing and data extracting was independently undertaken by two reviewers. A meta-analysis was performed to clarify the efficacy and safety of ticagrelor in general ACS patients, and a meta-regression analysis was taken to demonstrate the efficacy and safety of ticagrelor in DM patients compared with general ACS patients. Twenty-two studies with 35004 participants were included. The meta-analysis result implicated that ticagrelor could: 1) reduce the incidence of the composite endpoint [OR = 0.83, 95%CI (0.77, 0.90), P<0.00001] and the incidence of myocardial infarction [OR = 0.81, 95%CI (0.74, 0.89), P = 0.0001]; 2) not statistically reduce the incidence of cardiovascular death, the incidence of stroke and the incidence of bleeding events; 3) increase the incidence of dyspnea [OR = 1.90, 95%CI (1.73, 2.08), P<0.00001] compared with clopidogrel. Meanwhile, compared with prasugrel, ticagrelor could 1) reduce the platelet reactivity of patients at maintenance dose [MD = -44.59, 95%CI (-59.16, -30.02), P<0.00001]; 2) not statistically reduce the incidence of cardiovascular death, the platelet reactivity of patients 6 hours or 8 hours after administration, or the incidence of bleeding events; 3) induce the incidence of dyspnea [OR = 13.99, 95%CI (2.58, 75.92), P = 0.002]. Furthermore, the result of meta-regression analysis implicated that there was a positive correlation between DM patients and the platelet reactivity of patients 6 hours and 8 hours after administration, but there was no obvious correlation between DM patients and general ACS patients in other endpoints. Ticagrelor could reduce the incidence of composite endpoint of cardiovascular death, myocardial infarction and stroke as well as platelet reactivity in DM patients with ACS, while not increasing the risk of bleeding. Because there are differences in platelet reactivity between DM patients and general ACS patients, we suggest that caution is needed when using ticagrelor in clinical applications.

Autophagy is involved in TGF-β1-induced protective mechanisms and formation of cancer-associated fibroblasts phenotype in tumor microenvironment Autophagy is involved in TGF-β1-induced protective mechanisms and formation of cancer-associated fibroblasts phenotype in tumor microenvironment

Some apocynin analogues have exhibited outstanding inhibition to NADPH oxidase. In this study, the key interactions between apocynin analogues and NADPH oxidase were analyzed by the docking method. The potential active site was first identified by the SiteID program combining with the key residue CYS378. Afterwards, the compounds in the training set were docked into NADPH oxidase (1K4U) under specific docking constraints to discuss the key interactions between ligands and the receptor. These key interactions were then validated by the consistence between the docking result and the experimental result of the test set. The result reveals that the Pi interaction between apocynin analogues and NADPH oxidase has a direct contribution to inhibition activities, except for H-bond formation and docking score. The key interactions might be valuable to discover and screen apocynin analogues as potent inhibitors of NADPH oxidase.