Studies of Anticancer Activities In Vitro and In Vivo for Butyltin(IV)-Iridium(III) Imidazole-Phenanthroline Complexes with Aggregation-Induced Emission Properties.

Organotin(IV) and iridium(III) complexes have shown good application potential in the field of anticancer; however, the aggregation-caused quenching (ACQ) effect induced by high concentration or dose has limited the research on their targeting and anticancer mechanism. Then, a series of aggregation-induced emission (AIE)-activated butyltin(IV)-iridium(III) imidazole-phenanthroline complexes were prepared in this study. Complexes exhibited significant fluorescence improvement in the aggregated state because of the restricted intramolecular rotation (RIR), accompanied by an absolute fluorescence quantum yield of up to 29.2% (IrSn9). Complexes demonstrated potential in vitro antiproliferative and antimigration activity against A549 cells, following a lysosomal-mitochondrial apoptotic pathway. Nude mouse models further confirmed that complexes had favorable in vivo antitumor and antimigration activity in comparison to cisplatin. Therefore, butyltin(IV)-iridium(III) imidazole-phenanthroline complexes possess the potential as potential substitutes for platinum-based drugs.

Blockade of de novo pyrimidine biosynthesis triggers autophagic degradation of oncoprotein FLT3-ITD in acute myeloid leukemia.

The internal tandem duplication of the FMS-like tyrosine kinase 3 (FLT3-ITD) is one of the most frequent genetic alterations in acute myeloid leukemia (AML). Limited and transient clinical benefit of FLT3 kinase inhibitors (FLT3i) emphasizes the need for alternative therapeutic options for this subset of myeloid malignancies. Herein, we showed that FLT3-ITD mutant (FLT3-ITD+) AML cells were susceptible toward inhibitors of DHODH, a rate-limiting enzyme of de novo pyrimidine biosynthesis. Genetic and pharmacological blockade of DHODH triggered downregulation of FLT3-ITD protein, subsequently suppressed activation of downstream ERK and STAT5, and promoted cell death of FLT3-ITD+ AML cells. Mechanistically, DHODH blockade triggered autophagy-mediated FLT3-ITD degradation via inactivating mTOR, a potent autophagy repressor. Notably, blockade of DHODH synergized with an FDA-approved FLT3i quizartinib in significantly impairing the growth of FLT3-ITD+ AML cells and improving tumor-bearing mice survival. We further demonstrated that DHODH blockade exhibited profound anti-proliferation effect on quizartinib-resistant cells in vitro and in vivo. In summary, this study demonstrates that the induction of degradation of FLT3-ITD protein by DHODH blockade may offer a promising therapeutic strategy for AML patients harboring FLT3-ITD mutation.

Tiratricol, a thyroid hormone metabolite, has potent inhibitory activity against human dihydroorotate dehydrogenase.

Human dihydroorotate dehydrogenase (hDHODH) is a promising drug target for many diseases including autoimmune diseases, cancer, and viral infection. To develop more novel and potent hDHODH inhibitors, we screened our in-house library of old drugs. We found that tiratricol (3,3',5-triiodothyroacetic acid), a thyroid hormone metabolite, has potent hDHODH inhibitory activity (IC50 : 0.754 ± 0.126 µM), and its precursor tetrac (3,3',5,5'-tetraiodothyroacetic acid) also shows a certain inhibitory activity against hDHODH (IC50 : 11.960 ± 1.453 µM). Enzyme kinetic analysis shows that tiratricol and tetrac are noncompetitive inhibitors versus CoQ0 , which is different from the positive control A771726. ThermoFMN assay, molecular docking and site-directed mutagenesis all indicate that tiratricol and tetrac interact with more key residues of hDHODH than A771726, especially some hydrophobic residues in Subsite 1. In conclusion, our experiment results indicate a potential new use for the old drug, tiratricol, and provide a novel chemical scaffold for the design of hDHODH inhibitors.

wSDTNBI: a novel network-based inference method for virtual screening.

In recent years, the rapid development of network-based methods for the prediction of drug-target interactions (DTIs) provides an opportunity for the emergence of a new type of virtual screening (VS), namely, network-based VS. Herein, we reported a novel network-based inference method named wSDTNBI. Compared with previous network-based methods that use unweighted DTI networks, wSDTNBI uses weighted DTI networks whose edge weights are correlated with binding affinities. A two-pronged approach based on weighted DTI and drug-substructure association networks was employed to calculate prediction scores. To show the practical value of wSDTNBI, we performed network-based VS on retinoid-related orphan receptor γt (RORγt), and purchased 72 compounds for experimental validation. Seven of the purchased compounds were confirmed to be novel RORγt inverse agonists by in vitro experiments, including ursonic acid and oleanonic acid with IC50 values of 10 nM and 0.28 µM, respectively. Moreover, the direct contact between ursonic acid and RORγt was confirmed using the X-ray crystal structure, and in vivo experiments demonstrated that ursonic acid and oleanonic acid have therapeutic effects on multiple sclerosis. These results indicate that wSDTNBI might be a powerful tool for network-based VS in drug discovery.

[Application of the vacuum sealing drainage technique combined with skin flap in chronic ulcerative wounds].

OBJECTIVE: To explore the feasibility and efficacy of the vacuum sealing drainage (VSD) technique combined with skin flap for the treatment of chronic ulcerative wounds. METHODS: From June 2009 to Aug. 2011, the VSD technique combined with skin flap has been applied in the treatment of 15 patients with chronic ulcerative wounds caused by various reasons. The VSD was applied to the wound for 1-6 times. When infection was controlled and fresh granulation grew, skin flap was used to cover the wound. RESULTS: Flap necrosis happened in a small area at the distal end in one case, which healed after skin graft. All the other flaps survived with primary healing. The patients were followed up for 6-24 months postoperatively with no recurrence of infection. CONCLUSIONS: VSD combined with skin flap is an ideal choice for reconstruction of chronic ulcerative wounds. It has the advantages of low complications, reliable flap survival rate, and low infection recurrence.

[The change and significance of coagulation activity in bleomycin-induced lung fibrosis in rats].

OBJECTIVE: To investigate the role of coagulation activity of bronchoalveolar lavage fluid (BALF) in the pathogenesis of lung fibrosis. METHODS: Fourty-eight Sprague-Dawley rats were randomly divided into 2 groups, 24 rats in each group. In the bleomycin (BLM) group, the lung fibrosis model was made by tracheal instillation of bleomycin A(5) (BLMA(5), 5 mg/kg). At day 7, 14, 28 and 40, the recalcification time of normal pooled plasma, factor VII and X deficiency plasma were measured for procoagulation activity (PCA), and the thrombin activity and the protein level of transforming growth factor beta(1) (TGF-beta(1)) in BALF were also measured. In the control group, normal solution was instillated into the lungs. RESULTS: In the BLM group, the recalcification time of normal pooled plasma in BALF at the four time points were (56 +/- 10), (78 +/- 4), (172 +/- 11) and (180 +/- 6) s respectively, while in the control group, were (190 +/- 10), (186 +/- 8), (184 +/- 6) and (185 +/- 6) s respectively. The thrombin activity at the four time points were (1.26 +/- 0.03), (0.82 +/- 0.05), (0.28 +/- 0.03) and (0.28 +/- 0.02) microg/ml respectively in the BLM group, but were (0.31 +/- 0.02), (0.32 +/- 0.03), (0.31 +/- 0.04) and (0.29 +/- 0.05) microg/ml respectively in the control group. The level of TGF-beta(1) at the four time points were (310 +/- 36), (220 +/- 30), (109 +/- 12) and (96 +/- 11) ng/ml respectively in the BLM group, but were (92 +/- 20), (94 +/- 12), (92 +/- 10) and (90 +/- 9) ng/ml respectively in the control group. The above measurements were significantly different in day 7 and 14 between the BLM group and the control group (P < 0.01), while the differences were not significant at day 28 and 40 (P > 0.01). In the BLM group, at day 7 and 14, the recalcification time of factor VII deficiency plasma was (123 +/- 12) and (162 +/- 4) s respectively; the recalcification time of factor X deficiency plasma was (357 +/- 22) and (387 +/- 12) s respectively; the recalcification time of factor X deficiency plasma was longer than that of factor VII deficiency plasma and that of normal pooled plasma. Within 14 day, the level of TGF-beta(1) was positively correlated with PCA and thrombin activity. CONCLUSIONS: During the period of alveolitis, the PCA and thrombin activity were upregulated in BALF, which was caused by activated factor VII activating factor X and the switching to the exogenous coagulation pathway. But during the period of lung fibrosis, their activities were not upregulated. These results suggest that the coagulation factor and thrombin might contribute to the development of pulmonary fibrosis by promoting production of TGF-beta(1).