Theranostic systems are receiving ever-increasing attention due to their potential therapeutic utility, imaging enhancement capability, and promise for advancing the field of personalized medicine, particularly as it relates to the diagnosis, staging, and treatment of cancer. In this Tutorial Review, we provide an introduction to the concepts of theranostic drug delivery effected via use of conjugates that are able to target cancer cells selectively, provide cytotoxic chemotherapeutics, and produce readily monitored imaging signals in vitro and in vivo. The underlying design concepts, requiring the synthesis of conjugates composed of imaging reporters, masked chemotherapeutic drugs, cleavable linkers, and cancer targeting ligands, are discussed. Particular emphasis is placed on highlighting the potential benefits of fluorogenic reaction-based targeted systems that are activated for both imaging and therapy by cellular entities, e.g., thiols, reactive oxygen species and enzymes, which are present at relatively elevated levels in tumour environments, physiological characteristics of cancer, e.g., hypoxia and acidic pH. Also discussed are systems activated by an external stimulus, such as light. The work summarized in this Tutorial Review will help define the role fluorogenic reaction-based, cancer-targeting theranostics may have in advancing drug discovery efforts, as well as improving our understanding of cellular uptake and drug release mechanisms.

Transcriptional activation of eukaryotic genes depends on the precise and ordered recruitment of activators, chromatin modifiers/remodelers, coactivators, and general transcription factors to the promoters of target genes. Using the human matrix metalloproteinase 9 (MMP-9) gene as a model system, we investigated the sequential assembly and dynamic formation of transcription complexes on a human promoter under the influence of mitogen signaling. We find that, coincident with activation of the MMP-9 gene, activators, chromatin remodeling complexes, and coactivators are recruited to the preassembled MMP-9 promoter in a stepwise and coordinated order, which is dependent on activation of MEK-1/extracellular signal-regulated kinase and NF-B signaling pathways. Conversely, corepressor complexes are released from the MMP-9 promoter after transcriptional activation. Histone modifications shift from repressive to permissive modifications concurrent with activation of the MMP-9 gene. Chromatin remodeling induced by Brg-1 is required for MMP-9 gene transcription, which is concomitant with initiation of transcription. Therefore, coordination of cell signaling, chromatin remodeling, histone modifications, and stepwise recruitment of transcription regulators is critical to precisely regulate MMP-9 gene transcription in a temporally and spatially dependent manner. Given the important role of MMP-9 in both normal development and pathological conditions, understanding MMP-9 gene regulation is of great relevance.Gene transcription in eukaryotic cells is controlled by protein complexes, including general and tissue-specific transcription factors, coregulators, chromatin-remodeling complexes, and complexes responsible for signal-specific histone modifications (26). As eukaryotic DNA is packaged into chromatin, generally a repressive structure for transcriptional activation, transcription in the context of chromatin requires remodeling processes to reconfigure the chromatin, so that activators, coactivators, and general transcription factors (GTFs) have access to promoters of target genes (12). Chromatin remodeling is dependent on either ATP-dependent chromatin-remodelingcomplex-induced structural modifications of nucleosomes or histone acetyltransferase-(HAT) and histone methyltransferase-mediated covalent modifications of the N-terminal tails of core histones (12). The SWI/SNF chromatin-remodeling complex can alter chromatin structure by either shifting nucleosomes along the DNA or twisting DNA to modulate the nucleosome structure (42). Brg-1 and Brm are two ATPase subunits of the SWI/SNF complex. Recruitment of the SWI/ SNF complex to target promoters requires protein-protein interactions through Brg-1 and other transcription regulators, as Brg-1 does not recognize sequence-specific DNA (21).

Chronic alcohol-induced liver disease results in inflammation, steatosis and increased oxidative and nitrosative damage to the mitochondrion. We hypothesized that targeting an antioxidant to the mitochondria would prevent oxidative damage and attenuate the steatosis associated with alcoholic liver disease. To test this we investigated the effects of mitochondria-targeted ubiquinone, MitoQ, (5 & 25 mg/kg/d for 4 weeks) in male Sprague-Dawley rats consuming ethanol using the Lieber-DeCarli diet with pair-fed controls. Hepatic steatosis, 3-nitrotyosine (3-NT), 4-hydroxynonenal (4-HNE), hypoxia inducible factor α (HIF1α) and the activity of the mitochondrial respiratory chain complexes were assessed. As reported previously, ethanol consumption resulted in hepatocyte ballooning, increased lipid accumulation in the form of micro and macrovesicular steatosis and induction of CYP2E1. MitoQ had a minor on the ethanol-dependent decrease in mitochondrial respiratory chain proteins and their activities, it did however decrease hepatic steatosis in ethanol consuming animals and prevented the ethanol-induced formation of 3-NT and 4-HNE. Interestingly, MitoQ completely blocks the increase in HIF1α in all ethanol-fed groups which has previously been demonstrated in cell culture models and shown to be essential in ethanol-dependent hepatosteatosis. These results demonstrate the antioxidant capacity of MitoQ in alleviating alcohol associated mitochondrial ROS and several downstream effects of ROS/RNS production such as inhibiting protein nitration and protein aldehyde formation and specifically ROS-dependant HIF1α stabilization.

Oxidative stress is caused by an imbalance between the antioxidant and the reactive oxygen species, which results in damage to cells or tissues. Recent studies have reported that oxidative stress is involved in obesity, in addition to many other human diseases and aging. A prospective, randomized, double-blind study was performed to investigate the effect of astaxanthin (ASX), which is known to be a potent antioxidant, on oxidative stress in overweight and obese adults in Korea. Twenty-three adults with BMI > 25.0 kg/m(2) enrolled in this study and were randomly assigned to two dose groups: ASX 5 mg and 20 mg once daily for 3 weeks. Malondialdehyde (MDA), isoprostane (ISP), superoxide dismutase (SOD) and total antioxidant capacity (TAC), as oxidative stress biomarkers, were measured at baseline and 1, 2 and 3 weeks after ASX administration. Compared with baseline, the MDA (by 34.6% and 35.2%) and ISP (by 64.9% and 64.7%) levels were significantly lowered, whereas SOD (by 193% and 194%) and TAC (by 121% and 125%) levels were significantly increased in two dose groups after the 3 week intervention. This study revealed that supplemental ASX for 3 weeks improved oxidative stress biomarkers by suppressing lipid peroxidation and stimulating the activity of the antioxidant defense system.