Oxidative toxicity in diabetes and Alzheimer’s disease: mechanisms behind ROS/ RNS generation

Reactive oxidative species (ROS) toxicity remains an undisputed cause and link between Alzheimer’s disease (AD) and Type-2 Diabetes Mellitus (T2DM). Patients with both AD and T2DM have damaged, oxidized DNA, RNA, protein and lipid products that can be used as possible disease progression markers. Although the oxidative stress has been anticipated as a main cause in promoting both AD and T2DM, multiple pathways could be involved in ROS production. The focus of this review is to summarize the mechanisms involved in ROS production and their possible association with AD and T2DM pathogenesis and progression. We have also highlighted the role of current treatments that can be linked with reduced oxidative stress and damage in AD and T2DM.     

Distribution of soluble epoxide hydrolase and of cytochrome P450 2C8, 2C9, and 2J2 in human tissues.

Soluble epoxide hydrolase (sEH) hydrolyzes a wide variety of endogenous and exogenous epoxides. Many of these epoxides are believed to be formed by cytochrome P450 epoxygenases. Here we report the distribution of sEH and cytochrome P450 epoxygenases 2C8, 2C9, and 2J2 by immunohistochemistry. A large number of different tissues from different organs were evaluated using high-throughput tissue microarrays. sEH was found in the liver, kidney, and in many other organs, including adrenals, pancreatic islets, pituitary gland, lymphoid tissues, muscles, certain vascular smooth muscles, and epithelial cells in the skin, prostatic ducts, and the gastrointestinal tract. Immunolabeling for sEH was highly specific for particular tissues and individual cell types. CYP2C9 was also found in almost all of these organs and tissues, suggesting that 2C9 and sEH are very similar in their tissue-specific patterns of expression. CYP2C8 and 2J2 were also widely distributed in human tissues but were less frequently associated with sEH. The results suggest potentially distinct pathways of endogenous fatty acid epoxide production and hydrolysis in a variety of human tissues.     

Numb Expression and Asymmetric versus Symmetric Cell Division in Distal Embryonic Lung Epithelium

Proper balance between self-renewal and differentiation of lung-specific progenitors is absolutely required for normal lung morphogenesis/regeneration. Therefore, understanding the behavior of lung epithelial stem/progenitor cells could identify innovative solutions for restoring normal lung morphogenesis and/or regeneration. The Notch inhibitor Numb is a key determinant of asymmetric or symmetric cell division and hence cell fate. Yet Numb proximal-distal expression pattern and symmetric versus asymmetric division are uncharacterized during lung epithelial development. Herein, the authors find that the cell fate determinant Numb is highly expressed and asymmetrically distributed at the apical side of distal epithelial progenitors and segregated to one daughter cell in most mitotic cells. Knocking down Numb in MLE15 epithelial cells significantly increased the number of cells expressing the progenitor cell markers Sox9/Id2. Furthermore, cadherin hole analysis revealed that most distal epithelial stem/progenitor cells in embryonic lungs divide asymmetrically; with their cleavage, planes are predicted to bypass the cadherin hole, resulting in asymmetric distribution of the cadherin hole to the daughter cells. These novel findings provide evidence for asymmetric cell division in distal epithelial stem/progenitor cells of embryonic lungs and a framework for future translationally oriented studies in this area.     

Chromium Status and Glucose Tolerance in Saudi Men With and Without Coronary Artery Disease

Chromium deficiency is associated with impaired glucose tolerance (IGT) and dyslipidemia. Hence, the objective of the current study was to investigate chromium status among Saudi men with and without established cardiovascular disease (CVD) and its relationship to glucose tolerance, lipid profile and other established CVD risk factors. We measured serum and urine chromium concentrations, fasted lipid profile, plasma glucose, and serum lipid peroxide in 130 Saudi men with an established history of myocardial infarction and 130 age-matched controls without established CVD. Patients with established CVD had higher serum triglycerides (p < 0.05) and plasma glucose (p < 0.0001) and lower serum and urinary chromium concentrations (p < 0.0001) than controls. Serum chromium was inversely correlated with plasma glucose among cases and controls (r = −0.189, p < 0.05 and r = −0.354, p < 0.00001, respectively). Plasma glucose (OR 1.127, CI 1.0–1.269, p < 0.05), serum chromium (OR 0.99, CI 0.985–0.995, p < 0.0001), and urinary chromium (OR 0.988, CI 0.981–0.995, p < 0.001) were independently associated with the presence of established coronary disease applying this model. While chromium metabolism appears to be altered in individuals with CVD, it is unclear whether chromium supplementation would be effective in CVD prevention among patients with IGT. This would need to be tested in long-term outcome trials.     

Structure of the heme/hemoglobin outer membrane receptor ShuA from Shigella dysenteriae: Heme binding by an induced fit mechanism

Shigella dysentriae and other Gram‐negative human pathogens are able to use iron from heme bound to hemoglobin for growing. We solved at 2.6 Å resolution the 3D structure of the TonB‐dependent heme/hemoglobin outer membrane receptor ShuA from S. dysenteriae. ShuA binds to hemoglobin and transports heme across the outer membrane. The structure consists of a C‐terminal domain that folds into a 22‐stranded transmembrane β‐barrel, which is filled by the N‐terminal plug domain. One distal histidine ligand of heme is located at the apex of the plug, exposed to the solvent. His86 is situated 9.86 Å apart from His420, the second histidine involved in the heme binding. His420 is in the extracellular loop L7. The heme coordination by His86 and His420 involves conformational changes. The comparisons with the hemophore receptor HasR of Serratia marcescens bound to HasA‐Heme suggest an extracellular induced fit mechanism for the heme binding. The loop L7 contains hydrophobic residues which could interact with the hydrophobic porphyring ring of heme. The energy required for the transport by ShuA is derived from the proton motive force after interactions between the periplasmic N‐terminal TonB‐box of ShuA and the inner membrane protein, TonB. In ShuA, the TonB‐box is buried and cannot interact with TonB. The structural comparisons with HasR suggest its conformational change upon the heme binding for interacting with TonB. The signaling of the heme binding could involve a hydrogen bond network going from His86 to the TonB‐box. Proteins 2010. © 2009 Wiley‐Liss, Inc.     

Modulation of the K(v)4.3 channel by syntaxin 1A

The SNARE protein syntaxin 1A (Syn1A) is known to inhibit delayed rectifier K(+) channels of the K(v)1 and K(v)2 families with heterogeneous effects on their gating properties. In this study, we explored whether Syn1A could directly modulate K(v)4.3, a rapidly inactivating K(v) channel with important roles in neuroendocrine cells and cardiac myocytes. Immunoprecipitation studies in HEK293 cells coexpressing Syn1A and K(v)4.3 revealed a direct interaction with increased trafficking to the plasma membrane without a change in channel synthesis. Paradoxically, Syn1A inhibited K(v)4.3 current density. In particular, Syn1A produced a left-shift in steady-state inactivation of K(v)4.3 without affecting either voltage dependence of activation or gating kinetics, a pattern distinct from other K(v) channels. Combined with our previous reports, our results further verify the notion that the mechanisms involved in Syn1A-K(v) interactions vary significantly between K(v) channels, thus providing a wide scope for Syn1A modulation of exocytosis and membrane excitability.     

Nucleic acid-based vaccine for ovarian cancer cells; bench to bedside

Ovarian cancer continues to be a difficult medical issue that affects millions of individuals worldwide. Important platforms for cancer immunotherapy include checkpoint inhibitors, chimeric antigen receptor T cells, bispecific antibodies, cancer vaccines, and other cell-based treatments. To avoid numerous infectious illnesses, conventional vaccinations based on synthetic peptides, recombinant subunit vaccines, and live attenuated and inactivated pathogens are frequently utilized. Vaccine manufacturing processes, however, are not entirely safe and carry a significant danger of contaminating living microorganisms. As a result, the creation of substitute vaccinations is required for both viral and noninfectious illnesses, including cancer. Recently, there has been testing of nucleic acid vaccines, or NAVs, as a cancer therapeutic. Tumor antigens (TAs) are genetically encoded by DNA and mRNA vaccines, which the host uses to trigger immune responses against ovarian cancer cells that exhibit the TAs. Despite being straightforward, safe, and easy to produce, NAVs are not currently thought to be an ideal replacement for peptide vaccines. Some obstacles to this strategy include selecting the appropriate therapeutic agents (TAs), inadequate immunogenicity, and the immunosuppressive characteristic of ovarian cancer. We focus on strategies that have been employed to increase NAVs' effectiveness in the fight against ovarian cancer in this review.