Implications of the kynurenine pathway and quinolinic acid in Alzheimer's disease

Summary

Ozone, though not a free radical species, mediates its toxic effects through free radical reactions as a consequence of its high redox potential. Upon inspiration the first physical interface encountered by ozone is a thin layer of aqueous material, the epithelium lining fluid (ELF) which overlays, and is partially derived from, the underlying pulmonary epithelium. ELF is the first physical interface encountered by ozone and the majority of its primary actions are confined to this compartment. ELF contains a range of antioxidants, including the small molecular weight antioxidants: uric acid (UA), ascorbic acid (AH₂) and reduced glutathione (GSH). These compounds are present in large quantities and display high intrinsic reactivities toward ozone, consistent with their role as sacrificial substrates in this setting. In this paper we examine the concept that antioxidants, in ELF, represent the first tier of defence against the oxidizing effects of ozone. Since the concentration of these antioxidants appears to differ between individuals, we propose that these protective substances may dictate, in part, an individual's sensitivity to oxidizing air pollutants such as ozone.     

Molecular diagnostics and personalized medicine in oncology: Challenges and opportunities

Increasing evidence demonstrates that target‐based agents are active only in molecularly selected populations of patients. Therefore, the identification of predictive biomarkers has become mandatory to improve the clinical development of these novel drugs. Mutations of the epidermal growth factor receptor (EGFR) or rearrangements of the ALK gene in non‐small‐cell lung cancer, and BRAF mutations in melanoma are clear examples of driver mutations and predictive biomarkers of response to treatment with specific inhibitors. Predictive biomarkers might also identify subgroups of patients that are not likely to respond to specific drugs, as shown for KRAS mutations and anti‐EGFR monoclonal antibodies in colorectal carcinoma. The discovery of novel driver molecular alterations and the availability of drugs capable to selectively block such oncogenic mechanisms are leading to a rapid increase in the number of putative biomarkers that need to be assessed in each single patient. In this respect, two different approaches are being developed to introduce a comprehensive molecular characterization in clinical practice: high throughput genotyping platforms, which allow the detection of recognized genetic aberrations in clinical samples, and next generation sequencing that can provide information on all the different types of cancer‐causing alterations. The introduction of these techniques in clinical practice will increase the possibility to identify molecular targets in each individual patient, and will also allow to follow the molecular evolution of the disease during the treatment. By using these approaches, the development of personalized medicine for patients with cancer will finally become possible. J. Cell. Biochem. 114: 514–524, 2013. © 2012 Wiley Periodicals, Inc.     

Down‐regulation of c‐fos by shRNA sensitizes adriamycin‐resistant MCF‐7/ADR cells to chemotherapeutic agents via P‐glycoprotein inhibition and apoptosis augmentation

Multidrug resistance (MDR) is a major hurdle in the treatment of cancer. Research indicated that the main mechanisms of most cancers included so‐called “pump” (P‐glycoprotein, P‐gp) and “non‐pump” (apoptosis) resistance. Identification of novel signaling molecules associated with both P‐gp and apoptosis will facilitate the development of more effective strategies to overcome MDR in tumor cells. Since the proto‐oncogene c‐fos has been implicated in cell adaptation to environmental changes, we analyzed its role in mediating “pump” and “non‐pump” resistance in MCF‐7/ADR, an adriamycin (ADR)‐selected human breast cancer cell line with the MDR phenotype. Elevated expression of c‐fos in MCF‐7/ADR cells and induction of c‐fos by ADR in the parental drug‐sensitive MCF‐7 cells suggested a link between c‐fos and MDR phenotype. Down‐regulation of c‐fos expression via shRNA resulted in sensitization of MCF‐7/ADR cells to chemotherapeutic agents, including both P‐gp and non‐P‐gp substrates. Further results proved that c‐fos down‐regulation in MCF‐7/ADR cells resulted in decreased P‐gp expression and activity, enhanced apoptosis, and altered expression of apoptosis‐associated proteins (i.e., Bax, Bcl‐2, p53, and PUMA). All above facts indicate that c‐fos is involved in both P‐gp‐ and anti‐apoptosis‐mediated MDR of MCF‐7/ADR cells. Based on these results, we propose that c‐fos may represent a potential molecular target for resistant cancer therapy, and suppressing c‐fos gene expression may therefore be an effective means to temper breast cancer cell's MDR to cytotoxic chemotherapy. J. Cell. Biochem. 114: 1890–1900, 2013. © 2013 Wiley Periodicals, Inc.     

Founder cells regulate fiber number but not fiber formation during adult myogenesis in Drosophila

During insect myogenesis, myoblasts are organized into a pre-pattern by specialized organizer cells. In the Drosophila embryo, these cells have been termed founder cells and play important roles in specifying muscle identity and in serving as targets for myoblast fusion. A group of adult muscles, the dorsal longitudinal (flight) muscles, DLMs, is patterned by persistent larval scaffolds; the second set, the dorso-ventral muscles, DVMs is patterned by mono-nucleate founder cells (FCs) that are much larger than the surrounding myoblasts. Both types of organizer cells express Dumbfounded, which is known to regulate fusion during embryonic myogenesis. The role of DVM founder cells as well as the DLM scaffolds was tested in genetic ablation studies using the UAS/Gal4 system of targeted transgene expression. In both cases, removal of organizer cells prior to fusion, causes formation of supernumerary fibers, suggesting that cells in the myoblast pool have the capacity to initiate fiber formation, which is normally inhibited by the organizers. In addition to the large DVM FCs, some (smaller) cells in the myoblast pool also express Dumbfounded. We propose that these cells are responsible for seeding supernumerary fibers, when DVM FCs are eliminated prior to fusion. When these cells are also eliminated, myogenesis fails to occur. In the second set of studies, targeted expression of constitutively active Ras^V12 also resulted in the appearance of supernumerary fibers. In this case, the original DVM FCs are present, suggesting alterations in cell fate. Taken together, these data suggest that DVM myoblasts are able to respond to cues other than the original founder cell, to initiate fusion and fiber formation. Thus, the role of the large DVM founder cells is to generate the correct number of fibers, but they are not required for fiber formation itself. We also present evidence that the DVM FCs may arise from the leg imaginal disc.