Proton pump inhibitors (PPIs) are commonly used to treat acid-related diseases, most notably gastroesophageal reflux disease. PPIs are designed to shut down the gastric proton pump (H+/K+-ATPase) of parietal cells, thereby raising the pH of the stomach. While effective, a number of side effects have been associated with PPI use. Naturally occurring bacteria, some of which are acid-producing and contain ATPase enzymes, have also been found within the stomach, upper gastrointestinal tract, and oral cavity. Likewise, a number of fungi are known to inhabit the human body; some of these fungi contain H+-ATPase enzymes. Recent literature has suggested that PPIs may be inadvertently affecting these bacteria and fungi in two different ways: 1) PPIs may directly target the proton pumps of the bacteria and fungi, and/or 2) PPIs may indirectly affect the microenvironment of the flora via changes in pH. These unintended interactions are exasperated by the systemic distribution of PPIs throughout the body and may potentially lead to some of the side effects observed with PPI use. Herein we summarize what is currently known about the interactions between the PPIs and the natural human microbiota.

Magnetic resonance imaging (MRI) has long been used clinically and experimentally as a diagnostic tool to obtain three-dimensional, high resolution images of deep tissues. These images are enhanced by the administration of contrast agents such as paramagnetic Gd(III) complexes. Herein we describe the preparation of a series of multimodal imaging agents in which paramagnetic Gd(III) contrast agents are conjugated to a fluorescent tetrapyrrole, namely a porphyrazine (pz). Zinc metaled pzs conjugated to one, four, or eight paramagnetic Gd(III) complexes are reported. Among these conjugates, Zn-Pz-8Gd(III) exhibits an ionic relaxivity four times that of the monomeric Gd(III) agent, presumably because of increased molecular weight, and a molecular relaxivity that is approximately thirty times larger, while retaining the intense electronic absorption and emission of the unmodified pz. Unlike current clinical MR agents, ZnPz-1Gd(III) is taken up by cells. This probe demonstrates intracellular fluorescence by confocal microscopy and provides significant contrast enhancement in MR images, as well as marked phototoxicity in assays of cellular viability. These results suggest that pz agents possess a new potential for use in cancer imaging by both MRI and near-infrared (NIR) fluorescence, while acting as a platform for photodynamic therapy.

Nitric oxide (NO), a free radical, has been implicated in the biology of human cancers, including breast cancer, yet it is still unclear how NO affects tumor development and propagation. We herein gradually adapted four human breast adenocarcinoma cell lines (BT-20, Hs578T, T-47D, and MCF-7) to increasing concentrations of the NO donor DETA-NONOate up to 600 muM. The resulting model system consisted of a set of fully adapted high nitric oxide ("HNO") cell lines that are biologically different from the "parent" cell lines from which they originated. Although each of the four parent and HNO cell lines had identical morphologic appearance, the HNO cells grew faster than their corresponding parent cells and were resistant to both nitrogen- and oxygen-based free radicals. These cell lines serve as a novel tool to study the role of NO in breast cancer progression and potentially can be used to predict the therapeutic response leading to more efficient therapeutic regimens.