Human NQO1 as a Selective Target for Anticancer Therapeutics and Tumor Imaging.

Human NAD(P)H-quinone oxidoreductase1 (HNQO1) is a two-electron reductase antioxidant enzyme whose expression is driven by the NRF2 transcription factor highly active in the prooxidant milieu found in human malignancies. The resulting abundance of NQO1 expression (up to 200-fold) in cancers and a barely detectable expression in body tissues makes it a selective marker of neoplasms. NQO1 can catalyze the repeated futile redox cycling of certain natural and synthetic quinones to their hydroxyquinones, consuming NADPH and generating rapid bursts of cytotoxic reactive oxygen species (ROS) and H2O2. A greater level of this quinone bioactivation due to elevated NQO1 content has been recognized as a tumor-specific therapeutic strategy, which, however, has not been clinically exploited. We review here the natural and new quinones activated by NQO1, the catalytic inhibitors, and the ensuing cell death mechanisms. Further, the cancer-selective expression of NQO1 has opened excellent opportunities for distinguishing cancer cells/tissues from their normal counterparts. Given this diagnostic, prognostic, and therapeutic importance, we and others have engineered a large number of specific NQO1 turn-on small molecule probes that remain latent but release intense fluorescence groups at near-infrared and other wavelengths, following enzymatic cleavage in cancer cells and tumor masses. This sensitive visualization/quantitation and powerful imaging technology based on NQO1 expression offers promise for guided cancer surgery, and the reagents suggest a theranostic potential for NQO1-targeted chemotherapy.

Application of a Specific and Sensitive NQO1 Turn-On Near-Infrared Fluorescence Probe for Live Cancer Cell and Xenografted Tumor Imaging in Nude Mice.

Sensitive activity stains for enzymes selectively expressed in human cancers offer valuable tools for imaging with wide applications in experimental, diagnostic, and therapeutic settings. The scant expression of the antioxidant enzyme NQO1 in normal tissues and its great abundance in malignant counterparts due to the increased redox stress and hypoxia is one such example. Previously, we described a potent nontoxic probe that remains nonfluorescent but releases an intense fluorogenic compound after intracellular cleavage by NQO1 catalysis. This infrared probe with a 644 nm emission has excellent tissue penetrating ability and low background absorption. Described here are methods (fluorescence microscopy, flow cytometry, and in vivo animal imaging) to rapidly image NQO1 activity in hypoxic and non-hypoxic cancer cells and tumors developed in live mouse xenograft models. The specificity of the dye for NQO1 in all three procedures was verified, and the methods should be useful for both in vitro and in vivo studies.

Neurodevelopmental Outcomes in Children Born to Climate Refugee Mothers in Bangladesh: Experiences from Cyclone Aila.

Cyclone Aila hit the South-West coast of Bangladesh in May 2009, when in Dacope Upazilla over 50,000 people were left homeless as climate refugees (CRs) for over two years. We determined neurodevelopmental status of children born as CRs compared to their non-Climate Refugee (NCR) counterparts. Pregnant mothers were enrolled from May 2009 to April 2010 in entire Dacope in a study which profiled their health conditions. From among these mothers, 12 months post-Aila 267 CR mother-child dyads, and 552 NCR mother-child dyads were enrolled to assess their children's neurodevelopmental outcomes. There were significantly more landless families among CRs compared to NCRs (p value = 0.0001; OR = 1.86, 95% CI: 1.37 - 2.51). The mean±SD age at assessment of CR children was 8.52±4.57 months compared to a mean age 9.09±4.13 months of the NCR children (p=0.610). Neurodevelopmental Impairments (NDIs) were three times higher in the former (21.3%), compared to the latter (7.4%) group (p=0.0001; OR 3.83, 95% CI: 2.16 - 5.21). Specifically, expressive language (p value 0.002; OR 2.86, 95% CI: 1.46 - 5.57) and gross motor functions (p=0.007; OR 2.27, 95% CI 1.22 - 4.20) were the most significantly affected areas of impairment. Children born to CR mothers had a three times higher proportion of NDIs. The findings are of concern as in Bangladesh large populations are forced to leave their homes and become CRs annually. Optimum antenatal care of pregnant women as well as their offsprings within refugee situations needs to be ensured to prevent NDIs and poor quality of survival.

Drinking water vulnerability to climate change and alternatives for adaptation in coastal South and South East Asia.

Drinking water in much of Asia, particularly in coastal and rural settings, is provided by a variety of sources, which are widely distributed and frequently managed at an individual or local community level. Coastal and near-inland drinking water sources in South and South East (SSE) Asia are vulnerable to contamination by seawater, most dramatically from tropical cyclone induced storm surges. This paper assesses spatial vulnerabilities to salinisation of drinking water sources due to meteorological variability and climate change along the (ca. 6000 km) coastline of SSE Asia. The risks of increasing climatic stresses are first considered, and then maps of relative vulnerability along the entire coastline are developed, using data from global scale land surface models, along with an overall vulnerability index. The results show that surface and near-surface drinking water in the coastal areas of the mega-deltas in Vietnam and Bangladesh-India are most vulnerable, putting more than 25 million people at risk of drinking 'saline' water. Climate change is likely to exacerbate this problem, with adverse consequences for health, such as prevalence of hypertension and cardiovascular diseases. There is a need for identifying locations that are most at risk of salinisation in order for policy makers and local officials to implement strategies for reducing these health impacts. To counter the risks associated with these vulnerabilities, possible adaptation measures are also outlined. We conclude that detailed and fine scale vulnerability assessments may become crucial for planning targeted adaptation programmes along these coasts.

Role of tissue hypoxia as the mechanism of lactic acidosis during E. coli endotoxemia.

We compared the hemodynamic and metabolic alterations produced in rabbits by similar decreases in cardiac output created by inflating a balloon placed in the right ventricle (n = 6) with those produced by an intravenous bolus of Escherichia coli lipopolysaccharide (LPS; SEP group; n = 6). We measured O2 consumption (VO2), O2 transport (TO2), and O2 extraction ratio (ERO2) for the whole animal and also for the left hindlimb. Both groups experienced similar decreases in cardiac output, systemic TO2, and VO2 and similar increases in ERO2. For the hindlimb, TO2 was similar, but VO2 and ERO2 were lower for the SEP group 30 min after LPS administration (P less than 0.05); however, this difference disappeared during the remainder of the experiment. Arterial lactate concentration was greater (P less than 0.05) for the SEP group. There were no differences in skeletal muscle PO2, measured with a multiwire surface electrode, or in cardiac and skeletal muscle concentrations of high-energy phosphates. We hypothesize that a direct effect of LPS on cellular metabolism may have resulted in greater arterial lactate concentration for the SEP group.