Design, synthesis and biological evaluation of a novel colchicine-magnolol hybrid for inhibiting the growth of Lewis lung carcinoma in Vitro and in Vivo

Colchicine is a bioactive alkaloid originally from Colchicum autumnale and possesses excellent antiproliferative activity. However, colchicine-associated severe toxicity, gastrointestinal side effects in particular, limits its further therapeutic use. In the current study, we thus designed and synthesized a novel hybrid (CMH) by splicing colchicine and magnolol, a multifunctional polyphenol showing favorable gastrointestinal protection. The antitumor activity of CMH in Lewis lung carcinoma (LLC) was then evaluated in vitro and in vivo. Biologically, CMH inhibited the growth of LLC cells with an IC50 of 0.26 μM, 100 times more potently than cisplatin (26.05 μM) did. Meanwhile, the cytotoxicity of CMH was 10-fold lower than that of colchicine in normal human lung cells (BEAS-2B). In C57BL/6 mice xenograft model, CMH (0.5 mg/kg) worked as efficacious as colchicine (0.5 mg/kg) to inhibit tumor growth and 2 times more potently than cisplatin (1 mg/kg). In terms of mortality, 7 out of 10 mice died in colchicine group (0.75 mg/kg), while no death was observed in groups receiving CMH or cisplatin at 0.75 mg/kg. Mechanistic studies using Western blot revealed that CMH dose-dependently suppressed the protein expression of phosphorylated ERK. Molecular docking analysis further indicated that CMH was well fitted in the colchicine binding site of tubulin and formed several hydrogen bonds with tubulin protein. These results enable our novel hybrid CMH as a potential antineoplastic agent with lower toxicity, and provide perquisites for further investigation to confirm the therapeutic potentiality of this novel hybrid

Down-regulation of TM4SF is associated with the metastatic potential of gastric carcinoma TM4SF members in gastric carcinoma

<p>Abstract</p> <p>Background</p> <p>The aim of this study was to clarify the clinical significance of TM4SF members CD9, CD63 and CD82 in human gastric carcinoma.</p> <p>Methods</p> <p>By employing RT-PCR and immunohistochemistry, we studied the expression of CD9, CD63 and CD82 in 49 paired tissue specimens of normal gastric mucosa and carcinoma. All tissues were obtained from patients who underwent curative surgery.</p> <p>Results</p> <p>All normal gastric epithelium and gastric ulcer tissues strongly expressed transcripts and proteins of CD9, CD63 and CD82 as compared with corresponding controls. We found a significant correlation between CD63 mRNA level and different pM statuses (P = 0.036). Carcinomas in M0 stage revealed a stronger expression of CD63 than carcinomas in M1 stage. Expression of CD9 protein was found significantly stronger in pN0, pM0 than in advanced pN stages (P = 0.03), pM1 (P = 0.013), respectively. We found the relationship between CD63 expression, gender (p = 0.09) and nodal status (p = 0.028), respectively. Additionally, advanced and metastasized tumor tissues revealed significantly down-regulated CD82 protein expression (p = 0.033 and p = 0, respectively), which correlated with the tumor pTNM stage (p = 0.001).</p> <p>Conclusion</p> <p>The reduction of CD9, CD63 and CD82 expression are indicators for the metastatic potential of gastric carcinoma cells. Unlike their expression in other tumor types, the constitutive expression of CD63 may indicate that this factor does play a direct role in human gastric carcinogenesis.</p

Fabrication of Micro-Scale Gratings by Nanosecond Laser and Its Applications for Deformation Measurements

This paper experimentally investigated the fabrication and optimization of micro-scale gratings formed by nanosecond laser etching. The mechanism of nanosecond laser processing and the geometric phase analysis (GPA) are discussed, and the factors influencing the fabrication process including laser energy, laser fluence, and ablation threshold of material, are experimentally studied. In order to eliminate the dependence of the processing parameters on the samples, depositing Al film on a sample before laser processing is proposed for the fabrication of high-quality gratings. The energy of the laser pulse is optimized for clear line etching on Al film considering the distance between adjacent lines of parallel gratings. The optimal energy of the laser pulse is 9.8 μJ, and the optimum fluence is 9.5 J/mm2 with the waist radius of the laser beam 25.7 μm. With the optimal parameters, experimental results indicate that the highest frequency of parallel gratings is about 30 lines/mm, with a line width of 29 μm, and the distance between two adjacent laser pulses being of 10 μm. By performing tensile tests, micro-scale gratings fabricated on specimens are experimentally verified. The verification tests prove that the proposed fabrication method for the micro-scale gratings in GPA measurements is reliable and applicable, and the micro-scale gratings can be fabricated in many areas of interest, such as the crack tip, for deformation measurements. Furthermore, the adhesion between the Al film and the tested sample is strong enough so that the pattern sticks well to the sample