Paradoxical roles of antioxidant enzymes:Basic mechanisms and health implications

Reactive oxygen species (ROS) and reactive nitrogen species (RNS) are generated from aerobic metabolism, as a result of accidental electron leakage as well as regulated enzymatic processes. Because ROS/RNS can induce oxidative injury and act in redox signaling, enzymes metabolizing them will inherently promote either health or disease, depending on the physiological context. It is thus misleading to consider conventionally called antioxidant enzymes to be largely, if not exclusively, health protective. Because such a notion is nonetheless common, we herein attempt to rationalize why this simplistic view should be avoided. First we give an updated summary of physiological phenotypes triggered in mouse models of overexpression or knockout of major antioxidant enzymes. Subsequently, we focus on a series of striking cases that demonstrate “paradoxical” outcomes, i.e., increased fitness upon deletion of antioxidant enzymes or disease triggered by their overexpression. We elaborate mechanisms by which these phenotypes are mediated via chemical, biological, and metabolic interactions of the antioxidant enzymes with their substrates, downstream events, and cellular context. Furthermore, we propose that novel treatments of antioxidant enzyme-related human diseases may be enabled by deliberate targeting of dual roles of the pertaining enzymes. We also discuss the potential of “antioxidant” nutrients and phytochemicals, via regulating the expression or function of antioxidant enzymes, in preventing, treating, or aggravating chronic diseases. We conclude that “paradoxical” roles of antioxidant enzymes in physiology, health, and disease derive from sophisticated molecular mechanisms of redox biology and metabolic homeostasis. Simply viewing antioxidant enzymes as always being beneficial is not only conceptually misleading but also clinically hazardous if such notions underpin medical treatment protocols based on modulation of redox pathways

Quantum Correlations in NMR systems

In conventional NMR experiments, the Zeeman energy gaps of the nuclear spin ensembles are much lower than their thermal energies, and accordingly exhibit tiny polarizations. Generally such low-purity quantum states are devoid of quantum entanglement. However, there exist certain nonclassical correlations which can be observed even in such systems. In this chapter, we discuss three such quantum correlations, namely, quantum contextuality, Leggett-Garg temporal correlations, and quantum discord. In each case, we provide a brief theoretical background and then describe some results from NMR experiments.Comment: 21 pages, 7 figure

Synthesis, Infra-red, Raman, NMR and structural characterization by X-ray Diffraction of [C12H17N2]2CdCl4 and [C6H10N2]2Cd3Cl10 compounds

The synthesis, infra-red, Raman and NMR spectra and crystal structure of 2, 4, 4- trimethyl-4, 5- dihydro-3H-benzo[b] [1, 4] diazepin-1-ium tetrachlorocadmate, [C12H17N2]2CdCl4 and benzene-1,2-diaminium decachlorotricadmate(II) [C6H10N2]2Cd3Cl10 are reported. The [C12H17N2]2CdCl4 compound crystallizes in the triclinic system (P-1 space group) with Z = 2 and the following unit cell dimensions: a = 9.6653(8) angstrom, b = 9.9081(9) angstrom, c = 15.3737(2) angstrom, alpha = 79.486(1)degrees, beta = 88.610(8)degrees and gamma = 77.550(7)degrees. The structure was solved by using 4439 independent reflections down to R value of 0.029. In crystal structure, the tetrachlorocadmiate anion is connected to two organic cations through N-H...Cl hydrogen bonds and Van Der Waals interaction as to build cation-anion-cation cohesion. The [C6H10N2]2Cd3Cl10 crystallizes in the triclinic system (P-1 space group). The unit cell dimensions are a = 6.826 (5)angstrom, b = 9.861 (7)angstrom, c = 10.344 (3)angstrom, alpha = 103.50 (1)degrees, beta = 96.34 (4)degrees and gamma = 109.45 (3)degrees, Z=2. The final R value is 0.053 (Rw=0.128). Its crystal structure consists of organic cations and polymeric chains of [Cd3Cl10]4- anions running along the [011] direction, In The [C6H10N2]2Cd3Cl10 compounds hydrogen bond interactions between the inorganic chains and the organic cations, contribute to the crystal packing. PACS Codes: 61.10.Nz, 61.18.Fs, 78.30.-jComment: 19 pages, 10 figure

Effect of Lactobacillus acidophilus supernatants on body weight and leptin expression in rats

<p>Abstract</p> <p>Background</p> <p><it>Lactobacillus </it>extracts and supernatants have been used as probiotics in human and veterinary medicine for their ability to enhance wound healing and immunity. Previous data from our laboratory demonstrated that <it>Lactobacillus </it>supernatant (LS) stimulated wound healing, angiogenesis and proliferation of embryonic cells after topical application. This current study shows that LS after its administration into the cerebral ventricles of male rats exerts systemic effects.</p> <p>Methods</p> <p>The right lateral cerebral ventricle of young male rats was accessed through intracerebroventricular cannulation (ICV) under anesthesia and aseptic conditions. One group of control rats received saline solution, a second control group received 0.8 M lactic acid solution (to control for acidity of LS), and a third group received LS. The animals were sacrificed 12, 24, 48, 96 and 120 hours after the injection. Selected tissues were collected, fixed in 10% buffered formalin and used for immunohistochemistry and <it>in situ </it>hybridization. Other tissues were frozen and extracted for immunoblotting</p> <p>Results</p> <p>LS-injected animals had a slight decrease in body weight when compared to their initial weight and to both control groups. Using immunohistochemistry and <it>in situ </it>hybridization leptin expression was studied in multiple brain sections and peripheral adipose tissue of control and LS-injected rats. Strong cytoplasmic stain was observed by both techniques in neurons of the cerebral cortex, thalamus, hypothalamus, hippocampus and, to lesser degree, in the cells of the choroid plexus in the LS-injected rats. Control animals demonstrated much less intense staining in neurons located in the same regions using immunohistochemistry and almost no staining with <it>in situ </it>hybridization technique. Adipose tissue exhibited slight presence of leptin in LS-treated animals. In contrast no immunohistochemical staining for GM-CSF and TNFα was observed in brains from control and treated rats. Western blotting showed mild increase in leptin and leptin receptors in intestines and retroperitoneal adipose tissues of LS-injected rats.</p> <p>Conclusion</p> <p>This study demonstrates that direct administration of LS into rat CNS leads to a decrease in body weight of rats and an increase in the expression of leptin in specific areas of the brain and retroperitoneal adipose tissue.</p

Prognostic and predictive value of clinical and biochemical factors in breast cancer patients with bone metastases receiving "metronomic" zoledronic acid

<p>Abstract</p> <p>Background</p> <p>To assess prognostic and predictive effects of clinical and biochemical factors in our published randomized study of a weekly low dose (metronomic arm) versus a conventional dosage of zoledronic acid (conventional arm) in breast cancer patients with bone metastases.</p> <p>Methods</p> <p>Treatment outcome of 60 patients with bone metastases were used to assess impacts of following potential prognostic factors, estrogen receptor status, lymph node status, 2 year-disease free interval (DFI), numbers of chemotherapy regimens administered, interventions, and serum levels of VEGF, N-telopeptide of type I collagen (NTx), CEA, and CA 15-3.</p> <p>Results</p> <p>In univariate analyses, patients pretreated with 2 or fewer chemotherapy regimens, ER-positive tumors, 3 or fewer lymph nodes, DFI of more than 2 years, serum VEGF of less than 500 pg/mL after 3 months of intervention, serum CEA and CA 15-3 of less than ULN, and baseline serum NTx of less than 18 nM BCE had significantly longer progression free survival (PFS). The multivariate analysis showed that ER positivity (hazard ratio [HR], 0.295; 95% confidence interval [CI], 0.141-0.618; P = 0.001), serum VEGF of less than 500 pg/mL after 3 months of intervention (HR, 2.220; 95% CI, 1.136-4.338; P = 0.020), baseline serum NTx of less than 18 nM BCE (HR, 2.842; 95% CI, 1.458-5.539; P = 0.001), and 2 or fewer chemotherapy regimens received (HR, 7.803; 95% CI, 2.884-21.112; P = 0.000) were associated with a better PFS. When evaluating the predictive effect of the biochemical factors, an interaction between NTx and zoledronic acid intervention was shown (P = 0.005). The HR of weekly low dose versus a conventional dosage of zoledronic acid was estimated to be 2.309 (99% CI, 1.067-5.012) in patients with baseline serum NTx of more than 18 nM BCE, indicating a superiority of weekly low dose of zoledronic acid.</p> <p>Conclusions</p> <p>ER, serum VEGF level after intervention, and numbers of chemotherapy regimens administered are prognostic but not predictive factors in breast cancer patients with bone metastases. Patients with baseline serum NTx of more than 18 nM BCE might benefit more from weekly low-dose of zoledronic acid.</p> <p>Trial registration</p> <p>ClinicalTrials.gov unique identifier: ClinicalTrials.gov: <a href="http://www.clinicaltrials.gov/ct2/show/NCT00524849">NCT00524849</a></p

Field of Attention for Instantaneous Object Recognition

BACKGROUND: Instantaneous object discrimination and categorization are fundamental cognitive capacities performed with the guidance of visual attention. Visual attention enables selection of a salient object within a limited area of the visual field; we referred to as "field of attention" (FA). Though there is some evidence concerning the spatial extent of object recognition, the following questions still remain unknown: (a) how large is the FA for rapid object categorization, (b) how accuracy of attention is distributed over the FA, and (c) how fast complex objects can be categorized when presented against backgrounds formed by natural scenes. METHODOLOGY/PRINCIPAL FINDINGS: To answer these questions, we used a visual perceptual task in which subjects were asked to focus their attention on a point while being required to categorize briefly flashed (20 ms) photographs of natural scenes by indicating whether or not these contained an animal. By measuring the accuracy of categorization at different eccentricities from the fixation point, we were able to determine the spatial extent and the distribution of accuracy over the FA, as well as the speed of categorizing objects using stimulus onset asynchrony (SOA). Our results revealed that subjects are able to rapidly categorize complex natural images within about 0.1 s without eye movement, and showed that the FA for instantaneous image categorization covers a visual field extending 20° × 24°, and accuracy was highest (>90%) at the center of FA and declined with increasing eccentricity. CONCLUSIONS/SIGNIFICANCE: In conclusion, human beings are able to categorize complex natural images at a glance over a large extent of the visual field without eye movement

DEP and AFO Regulate Reproductive Habit in Rice

Sexual reproduction is essential for the life cycle of most angiosperms. However, pseudovivipary is an important reproductive strategy in some grasses. In this mode of reproduction, asexual propagules are produced in place of sexual reproductive structures. However, the molecular mechanism of pseudovivipary still remains a mystery. In this work, we found three naturally occurring mutants in rice, namely, phoenix (pho), degenerative palea (dep), and abnormal floral organs (afo). Genetic analysis of them indicated that the stable pseudovivipary mutant pho was a double mutant containing both a Mendelian mutation in DEP and a non-Mendelian mutation in AFO. Further map-based cloning and microarray analysis revealed that dep mutant was caused by a genetic alteration in OsMADS15 while afo was caused by an epigenetic mutation in OsMADS1. Thus, OsMADS1 and OsMADS15 are both required to ensure sexual reproduction in rice and mutations of them lead to the switch of reproductive habit from sexual to asexual in rice. For the first time, our results reveal two regulators for sexual and asexual reproduction modes in flowering plants. In addition, our findings also make it possible to manipulate the reproductive strategy of plants, at least in rice

Identification of DreI as an Antiviral Factor Regulated by RLR Signaling Pathway

BACKGROUND:Retinoic acid-inducible gene I (RIG-I)-like receptors (RLRs) had been demonstrated to prime interferon (IFN) response against viral infection via the conserved RLR signaling in fish, and a novel fish-specific gene, the grass carp reovirus (GCRV)-induced gene 2 (Gig2), had been suggested to play important role in host antiviral response. METHODOLOGY/PRINCIPAL FINDINGS:In this study, we cloned and characterized zebrafish Gig2 homolog (named Danio rerio Gig2-I, DreI), and revealed its antiviral role and expressional regulation signaling pathway. RT-PCR, Western blot and promoter activity assay indicate that DreI can be induced by poly I:C, spring viremia of carp virus (SVCV) and recombinant IFN (rIFN), showing that DreI is a typical ISG. Using the pivotal signaling molecules of RLR pathway, including RIG-I, MDA5 and IRF3 from crucian carp, it is found that DreI expression is regulated by RLR cascade and IRF3 plays an important role in this regulation. Furthermore, promoter mutation assay confirms that the IFN-stimulated regulatory elements (ISRE) in the 5' flanking region of DreI is essential for its induction. Finally, overexpression of DreI leads to establish a strong antiviral state against SVCV and Rana grylio virus (RGV) infection in EPC (Epithelioma papulosum cyprinid) cells. CONCLUSIONS/SIGNIFICANCE:These data indicate that DreI is an antiviral protein, which is regulated by RLR signaling pathway

Effect of Angiogenesis Inhibitor Bevacizumab on Survival in Patients with Cancer: A Meta-Analysis of the Published Literature

Bevacizumab is a recombinant humanized monoclonal antibody against vascular endothelial growth factor which has been used in conjunction with other anti-cancer agents in the treatment of patients with many cancers. It remains controversial whether bevacizumab can prolong survival in cancer patients. This meta-analysis was therefore performed to evaluate effect of bevacizumab on survival in cancer patients. PubMed, EMBASE, and Web of Science databases were searched for English-language studies of randomized controlled trials comparing bevacizumab with control therapy published through February 8, 2012. Progression-free survival, overall survival, and one-year survival rate were analyzed using random- or fixed-effects model. Thirty one assessable randomized controlled trials were identified. A significant improvement in progression-free survival in cancer patients was attributable to bevacizumab compared with control therapy (hazard ratio, 0.72; 95% confidence interval, 0.68 to 0.76; p<0.001). Overall survival was also significantly longer in patients were treated with bevacizumab (hazard ratio, 0.87; 95% confidence interval, 0.83 to 0.91; p<0.001). The significant benefit in one-year survival rate was further seen in cancer patients receiving bevacizumab (odds ratio, 1.30; 95% confidence interval, 1.20 to 1.41; p<0.001). Current evidences showed that bevacizumab prolong progression-free survival and overall survival, and increase one-year survival rate in cancer patients as compared with control therapy