Optimized Attenuated Salmonella Typhimurium Suppressed Tumor Growth and Improved Survival in Mice.
2区 · 生物学
作者: Kang Liang ; Rui Zhang ; Haiyan Luo ; Jinlong Zhang ; Zhenyuan Tian ; Xiaofen Zhang ; Yulin Zhang ; Md Kaisar Ali ; Qingke Kong
The gram-negative facultative anaerobic bacteria Salmonella enterica serovar Typhimurium (hereafter S. Typhimurium) has always been considered as one candidate of anti-tumor agents or vectors for delivering drug molecules. In this study, we compared several widely studied S. Typhimurium strains in their anti-tumor properties aiming to screen out the best one for further optimization and use in cancer therapy. In terms of the motility, virulence and anti-tumor efficacy, the three strains 14028, SL1344, and UK-1 were similar and obviously better than LT-2, and UK-1 showed the best phenotypes among them. Therefore, the strain UK-1 (D) was selected for the following studies. Its auxotrophic mutant strain (D1) harboring ∆aroA and ∆purM mutations was further optimized through the modification of lipid A structure, generating a new strain named D2 with stronger immunostimulatory activity. Finally, the ∆asd derivative of D2 was utilized as one live vector to deliver anti-tumor molecules including the angiogenesis inhibitor endostatin and apoptosis inducer TRAIL and the therapeutic and toxic-side effects were evaluated in mouse models of colon carcinoma and melanoma. After intraperitoneal infection, engineered Salmonella bacteria equipped with endostatin and/or TRAIL significantly suppressed the tumor growth and prolonged survival of tumor-bearing mice compared to PBS or bacteria carrying the empty plasmid. Consistently, immunohistochemical studies confirmed the colonization of Salmonella bacteria and the expression of anti-tumor molecules inside tumor tissue, which were accompanied by the increase of cell apoptosis and suppression of tumor angiogenesis. These results demonstrated that the beneficial anti-tumor efficacy of attenuated S. Typhimurium bacteria could be improved through delivery of drug molecules with powerful anti-tumor activities.
2013-10-01·Journal of Antimicrobial Chemotherapy2区 · 医学
Influence of the MBC/MIC ratio on the antibacterial activity of vancomycin versus linezolid against methicillin-resistant Staphylococcus aureus isolates in a pharmacodynamic model simulating serum and soft tissue interstitial fluid concentrations reported in diabetic patients
2区 · 医学
作者: Gonzalez, Natalia ; Sevillano, David ; Alou, Luis ; Cafini, Fabio ; Gimenez, Maria-Jose ; Gomez-Lus, Maria-Luisa ; Prieto, Jose ; Aguilar, Lorenzo
To explore serum and tissue pharmacodynamics of linezolid versus vancomycin against methicillin-resistant Staphylococcus aureus (MRSA) clinical isolates with different MBC/MIC ratios.
Five strains (vancomycin MIC/MBCs, mg/L) were used: TOL-1 (2/≥64), TOL-2 (1/16), LT-1 and LT-2 (1/8) and NT (1/2). The linezolid MIC/MBC for all strains was 2/≥64 mg/L. A two-compartment dynamic computerized device was used (inocula 10(7) cfu/mL). Free concentrations obtained in serum and interstitial fluid with twice-daily regimens of 1 g of vancomycin or 600 mg of linezolid were simulated over 48 h. ABBCs (differences between control growth curves and killing curves of bacteria exposed to antibiotics; log10 cfu × h/mL) and log10 reductions in initial inocula were calculated.
In serum simulations, vancomycin (AUC0-24/MIC = 251.8 for TOL-1 and 503.6 for the remaining strains) was bacteriostatic against strains with MBC/MIC ≥8, but bactericidal against NT. In interstitial fluid simulations (AUC0-24/MIC = 54.6 for TOL-1 and 109.2 for the remaining strains), initial inocula grew in all cases. Linezolid, both in serum (AUC0-24/MIC = 87.0) and in interstitial fluid (AUC0-24/MIC = 130.6) simulations, reduced initial inocula ≥2.2 log10 for all strains (apart from LT-1 in serum simulations that showed a bacteriostatic profile). ABBCs were similar in serum and interstitial fluid with linezolid, but significantly lower in interstitial fluid simulations with vancomycin.
From the pharmacodynamic perspective (serum concentrations), vancomycin tolerance should include MBC/MIC ≥8 since strains exhibiting this ratio showed bacteriostatic profiles similar to those obtained with isolates with MBC/MIC ratios of 16 or 32. Insufficient concentrations of vancomycin at the simulated infected site were linked to bacteriological failure. Free concentrations of linezolid at the infection site pharmacodynamically covered MRSA.
2000-02-01·Journal of Cellular Physiology2区 · 生物学
NF-κB activation mediates the response of a subpopulation of basal uroepithelial cells to a cell wall component of Enterococcus faecalis
2区 · 生物学
作者: Elgavish, Ada
Earlier in vitro studies revealed that treatment of basal urothelial cells (UT) with lipoteichoic acid, a cell wall component of Enterococcus faecalis (LT-2), stimulated a subpopulation of quiescent cells with high proliferative potential to divide (Elgavish et al., 1996b, J Cell Physiol 169:42-51). Studies were consistent with the possibility that NO-mediated mechanisms were involved (Elgavish et al., 1996c, J Cell Physiol 169:66-77). We postulated that LT-2 may upregulate expression of iNOS. Promoters of the gene encoding iNOS, as well as genes encoding many cytokines, contain elements homologous to consensus sequences for the binding of the transcription factor NF-kappaB. Based on this, we postulated that: (1) NF-kappaB activation is an early event following exposure of basal UT to LT-2 and (2) NF-kappaB activation mediates basal UT proliferation triggered by LT-2. To test these hypotheses, UT maintained for 3 days under growth-restricting conditions, were treated with or without 25 microg/ml LT-2. Nuclear distribution of NF-kappaB, that is, activated NF-kappaB, was detected by immunofluorescence microscopy in a subpopulation of basal UT as early as 5-10 min after the beginning of the treatment. In contrast, LT-2 had no effect on cultures containing more differentiated UT. NF-kappaB activation preceded production of NO, since treatment with 25 microM hemoglobin, a potent inactivator of NO, did not prevent LT-2-triggered NF-kappaB activation. Treatment with 10 microM pyrrolidine dithiocarbamate (PDTC) inhibited LT-2-triggered activation of NF-kappaB and prevented the stimulatory effect of LT-2 on proliferation of basal UT. These findings support the possibility that NF-kappaB activation mediates basal UT proliferation triggered by LT-2.