Reactive oxygen species (ROS) are a byproduct of normal metabolism and have roles in cell signaling and homeostasis. Species include oxygen radicals and reactive nonradicals. Mechanisms exist that regulate cellular levels of ROS, as their reactive nature may otherwise cause damage to key cellular components including DNA, protein, and lipid. When the cellular antioxidant capacity is exceeded, oxidative stress can result. Pleiotropic deleterious effects of oxidative stress are observed in numerous disease states and are also implicated in a variety of drug-induced toxicities. In this paper, we examine the nature of ROS-induced damage on key cellular targets of oxidative stress. We also review evidence implicating ROS in clinically relevant, drug-related side effects including doxorubicin-induced cardiac damage, azidothymidine-induced myopathy, and cisplatin-induced ototoxicity.

Vesicular monoamine transporter 2 is important for the accumulation of monoamine neurotransmitters into synaptic vesicles and histamine transport into secretory vesicles of the enterochromaffin-like cell of the gastric corpus. In this study we have investigated the mechanisms regulating the transcriptional activation of the rat vesicular monoamine transporter 2 (VMAT2) promoter in gastric epithelial cells. Maintenance of basal levels of transcription was dependent on the presence of SP1, cAMP-response element (CRE), and overlapping AP2/SP1 consensus sequences within the region of promoter from ؊86 to ؉1 base pairs (bp). Gastrin stimulation increased transcriptional activity, and responsiveness was shown to be dependent on the CRE (؊33 to ؊26 bp) and AP2/SP1 (؊61 to ؊48 bp) consensus sites but independent of the SP1 site at ؊86 to ؊81 bp. Gastrininduced transcription was dependent on the cooperative interaction of an uncharacterized nuclear factor of ϳ23.3 kDa that bound to the putative AP2/SP1 site, CREbinding protein (CREB), and CREB-binding protein/ p300. Gastrin stimulation resulted in the increased binding of phosphorylated CREB to the promoter, but it did not result in the increased binding of the AP2/SP1-binding protein. The gastrin responsiveness of the promoter was shown to be dependent on both the protein kinase C and mitogen-activated protein kinase/extracellular signal-regulated kinase kinase-signaling pathways, which may converge on the AP2/SP1-binding protein.The transport protein vesicular monoamine transporter 2 (VMAT2) 1 plays a central role in cellular physiology. It is responsible for the accumulation of monoamine neurotransmitters into synaptic vesicles and has been implicated in the synthesis and storage of histamine in the interleukin-3-dependent cell line Ea3.123 (1-5). VMAT2 may play a significant role in locomotor stimulation and/or the behavioral reward produced by amphetamines, and malfunctions of monoamine transport have been implicated in psychiatric disease (6, 7).Studies on VMAT2 knockout mice support the idea that vesicular monoamine transport is important in maintaining neuronal function with heterozygote VMAT2ϩ/Ϫ mice having dysfunctional monoamine storage and release parameters (6,8). VMAT2 is also likely to mediate histamine transport into the secretory vesicles of the enterochromaffin-like cell (ECL) of the gastric corpus (2, 4, 9-11). In the rat stomach the ECL cell is tightly regulated by the peptide hormone gastrin, with gastrin stimulation leading to the release of histamine and the resultant production of gastric acid from the parietal cell (12-14). Histamine is synthesized within the cytosol of the ECL cell from L-histidine by the action of the enzyme L-histidine decarboxylase (HDC) (15) and is then sequestered by VMAT2 into secretory vesicles that are stabilized by chromogranin A (CgA), a multi-functional acidic protein expressed both in neuroendocrine cells and in ECL cells (16 -21). Evidence suggests that VMAT2 may be up-regulated to accommodate the increased histamin...

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Development of next-generation oncolytic viruses requires the design of vectors that are potently oncolytic, immunogenic in human tumors, and well tolerated in patients. Starting with a joint-region deleted herpes simplex virus 1 (HSV-1) to create large transgene capability, we retained a single copy of the ICP34.5 gene, introduced mutations in UL37 to inhibit retrograde axonal transport, and inserted cell-type-specific microRNA (miRNA) target cassettes in HSV-1 genes essential for replication or neurovirulence. Ten miRNA candidates highly expressed in normal tissues and with low or absent expression in malignancies were selected from a comprehensive profile of 800 miRNAs with an emphasis on protection of the nervous system. Among the genes essential for viral replication identified using a small interfering RNA (siRNA) screen, we selected ICP4, ICP27, and UL8 for miRNA attenuation where a single miRNA is sufficient to potently attenuate viral replication. Additionally, a neuron-specific miRNA target cassette was introduced to control ICP34.5 expression. This vector is resistant to type I interferon compared to ICP34.5-deleted oncolytic HSVs, and in cancer cell lines, the oncolytic activity of the modified vector is equivalent to its parental virus. In vivo , this vector potently inhibits tumor growth while being well tolerated, even at high intravenous doses, compared to parental wild-type HSV-1.

Osteoporosis is characterized by reduced bone density and strength. Bone mass peaks between age 30 and 40 and then declines. This can be accelerated by factors including menopause and insufficient dietary calcium. Hormone replacement therapy (HRT) is currently the standard treatment for osteoporosis. However, growing concern over potential side effects of HRT has driven a search for alternative therapies. A recent report 1 reveals a potential alternative to HRT: a gender-neutral synthetic steroid that increases bone mass and strength without affecting reproductive organs. This compound acts via a novel extranuclear sex steroid receptor signaling mechanism that has important implications for nuclear receptor biology and human health.