CXCL2/MIF-CXCR2 signaling promotes the recruitment of myeloid-derived suppressor cells and is correlated with prognosis in bladder cancer.

The accumulation of myeloid-derived suppressor cells (MDSCs) has been observed in solid tumors and is correlated with tumor progression; however, the underlying mechanism is still poorly understood. In this study, we identified a mechanism by which tumor cells induce MDSC accumulation and expansion in the bladder cancer (BC) microenvironment via CXCL2/MIF-CXCR2 signaling. Elevated expression of CXCL2 and MIF and an increased number of CD33+ MDSCs were detected in BC tissues, and these increases were significantly associated with advanced disease stage and poor patient prognosis (P<0.01). A positive association was observed between CXCL2 or MIF expression and the number of tumor-infiltrating CD33+ MDSCs (P<0.01). Subsequently, we demonstrated that CD45+CD33+CD11b+HLA-DR- MDSCs from fresh BC tissues displayed high levels of suppressive molecules, including Arg1, iNOS, ROS, PDL-1 and P-STAT3, and stronger suppression of T-cell proliferation. Interestingly, these CD45+CD33+CD11b+HLA-DR- MDSCs exhibited increased CXCR2 expression compared with that in peripheral blood from BC patients or healthy controls (P<0.05). Chemotaxis assay revealed that bladder cancer cell line J82 induced MDSC migration via CXCL2/MIF-CXCR2 signaling in vitro. Mechanistic studies demonstrated that J82-induced MDSC trafficking and CXCR2 expression were associated with increased phosphorylation of p38, ERK and p65. Conversely, inhibition of the phosphorylation of p38, ERK or p65 decreased J82-induced MDSC trafficking and CXCR2 expression. CXCL2/MIF-stimulated activation of the mitogen-activated protein kinase and nuclear factor kappa B pathways in MDSCs was MyD88 dependent. Overall, our results identify the CXCL2/MIF-CXCR2 axis as an important mediator in MDSC recruitment and as predictors and potential therapeutic targets in BC patients.

[Synthesis and antimicrobial activity of 7-acylamido-3-1, 2, 3-triazol-1-ylmethyl) cephalosporins].

In order to develop oral cephalosporin exhibiting broad-spectrum activity, a series of cephalosporin derivatives (VIII1-12) bearing 1, 2, 3-triazolymethyl substituents on the C3 position were synthesized. 7-Phenylacetamido-3-methyl-3-cephem-4-carboxylic acid (I) was employed as starting material and converted to VIII by procedures of esterification and oxidation, bromination, azido-substitution, dipolarcycloaddition, deprotection, cleavage, and condensation. Minimum inhibitory concentration (MIC) values in vitro showed that VIII2-4.9-11 had a wide antibacterial spectrum against Gram positive and Gram negative bacteria and possessed high activities. Further biological evaluation and the study of oral absorption for the six compounds will be performed.

[Synthesis of 7-(4,7-di-substituted coumarin-3-acetamido)cephalosporins].

Seventeen derivatives of 7-(4,7-di-substituted coumarin-3-acetamido)cephalosporins were synthesized with acid chloride method, Vilsmeier reagent method and mixed anhydride method. Isolation and purification were fulfilled with Sephadex LH-20 column chromatography and centrifugal-TLC technique. Their chemical structures were identified by elemental analysis, IR and 1HNMR spectrum. The preliminary antibacterial activity tests showed that these cephalosporin derivatives exhibited good activity against Gram-positive bacteria and individual Gram-negative bacteria. Further experiments in pharmacology will be made.

[Synthesis of 7-(1,7-disubstituted-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxamido) -cephalosporins].

A series of new 7-(1, 7-disubstituted-1, 4-dihydro-4-oxo-1, 8-naphthyridine-3-carboxamido)-cephalosporins has been prepared by acylation of the 7-amino group of 7-ADCA, 7-ACA, 7-ACT and 7-ACD with 1, 7-disubstituted-1, 4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid. Mixed carboxylic-carbonic anhydride method was adopted in the reactions. Isolation and purification were fulfilled with Sephadex LH-20 column chromatography and centrifugal-TLC technique. Twenty four new cephalosporin derivatives were synthesized. Their structures have been confirmed by elemental analysis, IR and 1HNMR. In preliminary In vitro antibacterial sensitivity tests, most of these new derivatives were found to show good sensitivity to Gram-positive bacteria. Bacteriostasis were also observed for some Gram-negative bacteria.

[Synthesis of 7 beta-(6-substituted-2-quinolone-3-acetamido)cephalosporins].

A series of new 7 beta-(6-substituted-2-quinolone-3-acetamido)cephalosporins has been prepared by acylation of the 7 beta-amino group of 7-ADCA, 7-ACA, 7-ACT and 7-ACD with 6-substituted-2-quinolone-3-acetic acids. CDI (N,N'-Carbonyldiimidazole) method was mainly adopted and active ester method was also employed in the reactions. Isolation and purification were fulfilled with the combined methods of Sephadex LH-20 column chromatography and centrifugal TLC technique. Sixteen new cephalosporin derivatives were synthesized. Their structures have been confirmed by elemental analysis, IR and 1HNMR. The preliminary in vitro antibacterial tests showed that these new compounds exhibited high activity to gram-positive and some negative bacteria. Bacteriostasis of most of the compounds was equal to cefazolin and sodium penicillin G. Compound III3, III4, III8, III10 and III11 possessed higher activity on the resistant Staphylococcus aureus S22 and Proteus vulgaris OX19 than cefazolin and sodium penicillin G. Further biological evaluation for these compounds is expected to be carried out.