Ciprofloxacin Modulates Cytokine/chemokine Profile in Serum, Improves Bone Marrow Repopulation, and Limits Apoptosis and Autophagy in Ileum After Whole Body Ionizing Irradiation Combined With Skin-Wound Trauma.

Ciprofloxacin modulates cytokine/chemokine profile in serum, improves bone marrow repopulation, and limits apoptosis and autophagy in ileum after whole body ionizing irradiation combined with skin-wound trauma.

PLoS One. 2013; 8(3): e58389
Fukumoto R, Cary LH, Gorbunov NV, Lombardini ED, Elliott TB, Kiang JG

Radiation combined injury (CI) is a radiation injury (RI) combined with other types of injury, which generally leads to greater mortality than RI alone. A spectrum of specific, time-dependent pathophysiological changes is associated with CI. Of these changes, the massive release of pro-inflammatory cytokines, severe hematopoietic and gastrointestinal losses and bacterial sepsis are important treatment targets to improve survival. Ciprofloxacin (CIP) is known to have immunomodulatory effect besides the antimicrobial activity. The present study reports that CIP ameliorated pathophysiological changes unique to CI that later led to major mortality. B6D2F1/J mice received CI on day 0, by RI followed by wound trauma, and were treated with CIP (90 mg/kg p.o., q.d. within 2 h after CI through day 10). At day 10, CIP treatment not only significantly reduced pro-inflammatory cytokine and chemokine concentrations, including interleukin-6 (IL-6) and KC (i.e., IL-8 in human), but it also enhanced IL-3 production compared to vehicle-treated controls. Mice treated with CIP displayed a greater repopulation of bone marrow cells. CIP also limited CI-induced apoptosis and autophagy in ileal villi, systemic bacterial infection, and IgA production. CIP treatment led to LD0/10 compared to LD20/10 for vehicle-treated group after CI. Given the multiple beneficial activities of CIP shown in our experiments, CIP may prove to be a useful therapeutic drug for CI. HubMed – drug


Metabolic adaptation to chronic inhibition of mitochondrial protein synthesis in acute myeloid leukemia cells.

PLoS One. 2013; 8(3): e58367
Jhas B, Sriskanthadevan S, Skrtic M, Sukhai MA, Voisin V, Jitkova Y, Gronda M, Hurren R, Laister RC, Bader GD, Minden MD, Schimmer AD

Recently, we demonstrated that the anti-bacterial agent tigecycline preferentially induces death in leukemia cells through the inhibition of mitochondrial protein synthesis. Here, we sought to understand mechanisms of resistance to tigecycline by establishing a leukemia cell line resistant to the drug. TEX leukemia cells were treated with increasing concentrations of tigecycline over 4 months and a population of cells resistant to tigecycline (RTEX+TIG) was selected. Compared to wild type cells, RTEX+TIG cells had undetectable levels of mitochondrially translated proteins Cox-1 and Cox-2, reduced oxygen consumption and increased rates of glycolysis. Moreover, RTEX+TIG cells were more sensitive to inhibitors of glycolysis and more resistant to hypoxia. By electron microscopy, RTEX+TIG cells had abnormally swollen mitochondria with irregular cristae structures. RNA sequencing demonstrated a significant over-representation of genes with binding sites for the HIF1?:HIF1? transcription factor complex in their promoters. Upregulation of HIF1? mRNA and protein in RTEX+TIG cells was confirmed by Q-RTPCR and immunoblotting. Strikingly, upon removal of tigecycline from RTEX+TIG cells, the cells re-established aerobic metabolism. Levels of Cox-1 and Cox-2, oxygen consumption, glycolysis, mitochondrial mass and mitochondrial membrane potential returned to wild type levels, but HIF1? remained elevated. However, upon re-treatment with tigecycline for 72 hours, the glycolytic phenotype was re-established. Thus, we have generated cells with a reversible metabolic phenotype by chronic treatment with an inhibitor of mitochondrial protein synthesis. These cells will provide insight into cellular adaptations used to cope with metabolic stress. HubMed – drug


Detection of drug-drug interactions by modeling interaction profile fingerprints.

PLoS One. 2013; 8(3): e58321
Vilar S, Uriarte E, Santana L, Tatonetti NP, Friedman C

Drug-drug interactions (DDIs) constitute an important problem in postmarketing pharmacovigilance and in the development of new drugs. The effectiveness or toxicity of a medication could be affected by the co-administration of other drugs that share pharmacokinetic or pharmacodynamic pathways. For this reason, a great effort is being made to develop new methodologies to detect and assess DDIs. In this article, we present a novel method based on drug interaction profile fingerprints (IPFs) with successful application to DDI detection. IPFs were generated based on the DrugBank database, which provided 9,454 well-established DDIs as a primary source of interaction data. The model uses IPFs to measure the similarity of pairs of drugs and generates new putative DDIs from the non-intersecting interactions of a pair. We described as part of our analysis the pharmacological and biological effects associated with the putative interactions; for example, the interaction between haloperidol and dicyclomine can cause increased risk of psychosis and tardive dyskinesia. First, we evaluated the method through hold-out validation and then by using four independent test sets that did not overlap with DrugBank. Precision for the test sets ranged from 0.4-0.5 with more than two fold enrichment factor enhancement. In conclusion, we demonstrated the usefulness of the method in pharmacovigilance as a DDI predictor, and created a dataset of potential DDIs, highlighting the etiology or pharmacological effect of the DDI, and providing an exploratory tool to facilitate decision support in DDI detection and patient safety. HubMed – drug