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Regulatory Role of NADPH Oxidase 2 in the Polarization Dynamics and Neurotoxicity of Microglia/Macrophages after Traumatic Brain Injury.
Abstract Traumatic brain injury (TBI) is a leading cause of death and disability. Secondary injuries that develop after the initial trauma contribute to long-lasting neurophysiological deficits. Polarization of microglia/macrophages toward a pro-inflammatory (M1) phenotype may increase the progression of secondary injury following TBI; however, the regulatory and functional mechanisms underlying these changes remain poorly defined. In the present study, we showed elevated expression of NADPH oxidase 2 (NOX2) and activation of nuclear factor-kappa B (NF-κB) predominantly in microglia/macrophages at 4- and 7-d...
Source: Free Radical Biology and Medicine - September 20, 2017 Category: Biology Authors: Wang J, Ma MW, Dhandapani KM, Brann DW Tags: Free Radic Biol Med Source Type: research

Inhibition of hepatocyte nuclear factor 1b induces hepatic steatosis through DPP4/NOX1-mediated regulation of superoxide.
Abstract Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disorder that is closely associated with insulin resistance and type 2 diabetes. Previous studies have suggested that hepatocyte nuclear factor 1b (HNF1b) ameliorates insulin resistance. However, the role of HNF1b in the regulation of lipid metabolism and hepatic steatosis remains poorly understood. We found that HNF1b expression was decreased in steatotic livers. We injected mice with lentivirus (LV) expressing HNF1b shRNA to generate mice with hepatic knockdown of HNF1b. We also injected high fat (HF) diet-induced obese and db/db ...
Source: Free Radical Biology and Medicine - September 20, 2017 Category: Biology Authors: Long Z, Cao M, Su S, Wu G, Meng F, Wu H, Liu J, Yu W, Atabai K, Wang X Tags: Free Radic Biol Med Source Type: research

Theaflavin ameliorates ionizing radiation-induced hematopoietic injury via the NRF2 pathway.
In this study, we explored the potential role of TF in IR-induced HSC injury and the underlying mechanism in a total body irradiation (TBI) mouse model. Our results showed that TF improved survival of irradiated wild-type mice and ameliorated TBI-induced hematopoietic injury by attenuating myelosuppression and myeloid skewing, increasing HSC frequency, and promoting reconstitution of irradiated HSCs. Furthermore, TF inhibited TBI-induced HSC senescence. These effects of TF were associated with a decline in ROS levels and DNA damage in irradiated HSCs. TF reduced oxidative stress mainly by up-regulating nuclear factor eryth...
Source: Free Radical Biology and Medicine - September 19, 2017 Category: Biology Authors: Han X, Zhang J, Xue X, Zhao Y, Lu L, Cui M, Miao W, Fan S Tags: Free Radic Biol Med Source Type: research

Suppressed ubiquitination of Nrf2 by p47(phox) contributes to Nrf2 activation.
Abstract Although critical in phagocytosis in innate immunity, reactive oxygen species (ROS) collaterally inflict damage to host phagocytes because they indiscriminate targets. Since Nrf2 increases the expression of anti-oxidant enzymes that nullifies ROS, ROS activating Nrf2 is a critical negative regulatory step for countering the deleterious effects of ROS. Here, we postulate whether, along with ROS activating Nrf2, NADPH oxidase components also participate in direct activation of Nrf2, contributing to protection from ROS. Our results show that the p47(phox) of the NADPH oxidase, but not p65(phox) or p40(phox),...
Source: Free Radical Biology and Medicine - September 19, 2017 Category: Biology Authors: Ha Kim K, Sadikot RT, Yeon Lee J, Jeong HS, Oh YK, Blackwell TS, Joo M Tags: Free Radic Biol Med Source Type: research

Red/Near Infrared Light Stimulates Release of an Endothelium Dependent Vasodilator and Rescues Vascular Dysfunction in a Diabetes Model.
In conclusion, R/NIR stimulates vasodilation by release of NO bound substances from the endothelium. In a diabetes model of endothelial dysfunction, R/NIR restores vasodilation, which lends the potential for new treatments for diabetic vascular disease. PMID: 28935419 [PubMed - as supplied by publisher] (Source: Free Radical Biology and Medicine)
Source: Free Radical Biology and Medicine - September 18, 2017 Category: Biology Authors: Keszler A, Lindemer B, Weihrauch D, Jones D, Hogg N, Lohr NL Tags: Free Radic Biol Med Source Type: research

Down syndrome, beta-amyloid and neuroimaging.
Abstract This review focuses on the role of Aβ in AD pathogenesis in Down syndrome and current approaches for imaging Aβ in vivo. We will describe how Aβ deposits with age, the posttranslational modifications that can occur, and detection in biofluids. Three unique case studies describing partial trisomy 21 cases without APP triplication, and the occurrences of low level mosaic trisomy 21 in an early onset AD patient are presented. Brain imaging for Aβ includes those by positron emission tomography and ligands (Pittsburgh Compound B, Florbetapir, and FDDNP) that bind Aβ have been published...
Source: Free Radical Biology and Medicine - September 18, 2017 Category: Biology Authors: Head E, Helman A, Powell D, Schmitt F Tags: Free Radic Biol Med Source Type: research

Insulin-dependent metabolic and inotropic responses in the heart are modulated by hydrogen peroxide from NADPH-oxidase isoforms NOX2 and NOX4.
CONCLUSIONS: These studies identify a proximal point of bifurcation in cardiac insulin signaling through the simultaneous activation of both NOX2 and NOX4. Each NOX isoform generates H2O2 in cardiac myocytes with distinct time courses, with H2O2 derived from NOX2 augmenting Akt-dependent metabolic effects of insulin, while H2O2 from NOX4 blocks beta adrenergic increases in inotropy. These findings suggest that insulin resistance in the diabetic heart may lead to potentially deleterious potentiation of beta adrenergic responses. PMID: 28917508 [PubMed - as supplied by publisher] (Source: Free Radical Biology and Medicine)
Source: Free Radical Biology and Medicine - September 13, 2017 Category: Biology Authors: Steinhorn B, Sartoretto JL, Sorrentino A, Romero N, Kalwa H, Dale Abel E, Michel T Tags: Free Radic Biol Med Source Type: research

Characterizing thiol redox dynamics in the organogenesis stage rat embryo.
In this study, we characterize and connect thiol redox dynamics, protein synthesis, volumetric growth and net cysteine fluxes over the course of early organogenesis (gestational day (GD) 10 to GD11.13) in the rat embryo. Our results show that despite a significant exponential growth of conceptal volumes and protein mass, the GSH:GSSG redox balance is remarkably stable during early organogenesis, with distinct redox potentials for the visceral yolk sac (VYS) (-218mV) and the embryo proper (EMB) (-222mV). The yolk sac was found to play a key role in maintaining GSH levels and the GSH:GSSG redox balance in the developing embr...
Source: Free Radical Biology and Medicine - September 12, 2017 Category: Biology Authors: Veltman K, Ahmad Y, Harris C, Jolliet O Tags: Free Radic Biol Med Source Type: research

Down-regulation of NOX2 activity in phagocytes mediated by ATM-kinase dependent phosphorylation.
sia M Abstract NADPH oxidases (NOX) have many biological roles, but their regulation to control production of potentially toxic ROS molecules remains unclear. A previously identified insertion sequence of 21 residues (called NIS) influences NOX activity, and its predicted flexibility makes it a good candidate for providing a dynamic switch controlling the NOX active site. We constructed NOX2 chimeras in which NIS had been deleted or exchanged with those from other NOXs (NIS1, 3 and 4). All contained functional heme and were expressed normally at the plasma membrane of differentiated PLB-985 cells. However, NOX2-&D...
Source: Free Radical Biology and Medicine - September 12, 2017 Category: Biology Authors: Beaumel S, Picciocchi A, Debeurme F, Vives C, Hesse AM, Ferro M, Grunwald D, Stieglitz H, Thepchatri P, Smith SME, Fieschi F, José Stasia M Tags: Free Radic Biol Med Source Type: research

Nox4 regulates the eNOS uncoupling process in aging endothelial cells.
Abstract ROS and its associated signaling contribute to vascular aging-associated endothelial disturbance. Since the non-effective endothelial nitric oxide synthase (eNOS) coupling status is related to vascular aging-related phenotypes, eNOS coupled/uncoupled system signaling was studied in human umbilical vein endothelial cells (HUVEC). Nitric oxide (NO) and eNOS Ser1177 were significantly decreased, whereas O2(-) (superoxide anion radical) increased with passage number. In aging cells, NADPH oxidase 4 (Nox4), one of the main superoxide generating enzymes, and its associated protein disulfide isomerase (PDI) chap...
Source: Free Radical Biology and Medicine - September 12, 2017 Category: Biology Authors: Lee HY, Kim HR, Chae HJ Tags: Free Radic Biol Med Source Type: research

Deletion of NADH oxidase in Listeria monocytogenes promotes the bacterial infection of brain.
In conclusion, our study evaluated the function of nox in L. monocytogenes and indicated that nox could regulate the invasion of L. monocytogenes by regulating virulence genes expression and the interaction of host-and- pathogens. PMID: 28916475 [PubMed - as supplied by publisher] (Source: Free Radical Biology and Medicine)
Source: Free Radical Biology and Medicine - September 12, 2017 Category: Biology Authors: Li S, Yu W, Guan X, Luo Z, Chen G, Liu W, Zhang J Tags: Free Radic Biol Med Source Type: research

Pharmacologic ascorbate induces neuroblastoma cell death by hydrogen peroxide mediated DNA damage and reduction in cancer cell glycolysis.
Abstract An ascorbate-mediated production of oxidative stress has been shown to retard tumor growth. Subsequent glycolysis inhibition has been suggested. Here, we further define the mechanisms relevant to this observation. Ascorbate was cytotoxic to human neuroblastoma cells through the production of H2O2, which led to ATP depletion, inhibited GAPDH, and non-apoptotic and non-autophagic cell death. The mechanism of cytotoxicity is different when PARP-dependent DNA repair machinery is active or inhibited. Ascorbate-generated H2O2 damaged DNA, activated PARP, depleted NAD+, and reduced glycolysis flux. NAD+ suppleme...
Source: Free Radical Biology and Medicine - September 12, 2017 Category: Biology Authors: Ma E, Chen P, Wilkins HM, Wang T, Swerdlow RH, Chen Q Tags: Free Radic Biol Med Source Type: research

Melatonin-mediated upregulation of Sirt3 attenuates sodium fluoride-induced hepatotoxicity by activating the MT1-PI3K/AKT-PGC-1 α signaling pathway.
This study investigated the protective effects of melatonin pretreatment on NaF-induced hepatotoxicity and elucidates the potential mechanism of melatonin-mediated protection. Reducing mitochondrial ROS by melatonin substantially attenuated NaF-induced NADPH oxidase 4 (Nox4) upregulation and cytotoxicity in L-02 cells. Melatonin exerted its hepatoprotective effects by upregulating Sirtuin 3 (Sirt3) expression level and its activity. Melatonin increased the activity of manganese superoxide dismutase (SOD2) by promoting Sirt3-mediated deacetylation and promoted SOD2 expression through Sirt3-regulated DNA-binding activity of ...
Source: Free Radical Biology and Medicine - September 11, 2017 Category: Biology Authors: Song C, Zhao J, Fu B, Dan Li, Mao T, Peng W, Wu H, Zhang Y Tags: Free Radic Biol Med Source Type: research

Nitric oxide donor [Ru(terpy)(bdq)NO](3+) induces uncoupling and phosphorylation of endothelial nitric oxide synthase promoting oxidant production.
Abstract [Ru(terpy)(bdq)NO](3+) (TERPY) is a nitric oxide (NO) donor that promotes relaxation of the mesenteric artery and aorta in rats. We sought to investigate whether it acts as both an NO donor and endothelial NO synthase (eNOS) activator, as shown previously for nitroglycerin. Human umbilical vein endothelial cells (HUVECs) and human embryonic kidney 293 cells transfected with empty vector (HEK) or eNOS cDNA (HEK-eNOS) were treated with TERPY (1µM) for different lengths of time. eNOS expression, dimerization, and Ser(1177) phosphorylation, caveolin-1 (Cav-1) oligomerization, Cav-1 Tyr(14) phosphorylati...
Source: Free Radical Biology and Medicine - September 9, 2017 Category: Biology Authors: Potje SR, Chen Z, Oliveira SDS, Bendhack LM, da Silva RS, Bonini MG, Antoniali C, Minshall RD Tags: Free Radic Biol Med Source Type: research

Low-Density Lipoprotein Docosahexaenoic Acid Nanoparticles Induce Ferroptotic Cell Death in Hepatocellular Carcinoma.
CONCLUSION: LDL-DHA induces cell death in HCC cells through the ferroptosis pathway, this represents a novel molecular mechanism of anticancer activity for LDL-DHA nanoparticles. PMID: 28893626 [PubMed - as supplied by publisher] (Source: Free Radical Biology and Medicine)
Source: Free Radical Biology and Medicine - September 8, 2017 Category: Biology Authors: Ou W, Mulik RS, Anwar A, McDonald JG, He X, Corbin IR Tags: Free Radic Biol Med Source Type: research

The caspase-8/Bid/cytochrome c axis links signals from death receptors to mitochondrial reactive oxygen species production.
Abstract Ligation of the death receptors for TNF-α, FasL, and TRAIL triggers two common pathways, caspase-dependent intrinsic apoptosis and intracellular reactive oxygen species (ROS) generation. The apoptotic pathway is well characterized; however, a signaling linker between the death receptor and ROS production has not been clearly elucidated. Here, we found that death receptor-induced ROS generation was strongly inhibited by mitochondrial complex I and II inhibitors, but not by inhibitors of NADPH oxidase, lipoxygenase, cyclooxygenase or xanthine oxidase, indicating that ROS are mostly generated by the im...
Source: Free Radical Biology and Medicine - September 6, 2017 Category: Biology Authors: Kim WS, Lee KS, Kim JH, Kim CK, Lee G, Choe J, Won MH, Kim TH, Jeoung D, Lee H, Kim JY, Ae Jeong M, Ha KS, Kwon YG, Kim YM Tags: Free Radic Biol Med Source Type: research

Exosomal biomarkers in down syndrome and alzheimer's disease.
EXOSOMAL BIOMARKERS IN DOWN SYNDROME AND ALZHEIMER'S DISEASE. Free Radic Biol Med. 2017 Sep 04;: Authors: Hamlett ED, Ledreux A, Potter H, Chial HJ, Patterson D, Espinosa JM, Bettcher BM, Granholm AC Abstract Every person with Down syndrome (DS) has the characteristic features of Alzheimer's disease (AD) neuropathology in their brain by the age of forty, and most go on to develop AD dementia. Since people with DS show highly variable levels of baseline function, it is often difficult to identify early signs of dementia in this population. The discovery of blood biomarkers predictive of dementia onset ...
Source: Free Radical Biology and Medicine - September 4, 2017 Category: Biology Authors: Hamlett ED, Ledreux A, Potter H, Chial HJ, Patterson D, Espinosa JM, Bettcher BM, Granholm AC Tags: Free Radic Biol Med Source Type: research

The NO-heme signaling hypothesis.
Abstract While the biological role of nitric oxide (NO) synthase (NOS) is appreciated, several fundamental aspects of the NOS/NO-related signaling pathway(s) remain incompletely understood. Canonically, the NOS-derived NO diffuses through the (inter)cellular milieu to bind the prosthetic ferro(Fe(2+))-heme group of the soluble guanylyl cyclase (sGC). The formation of ternary NO-ferroheme-sGC complex results in the enzyme activation and accelerated production of the second messenger, cyclic GMP. This paper argues that cells dynamically generate mobile/exchangeable NO-ferroheme species, which activate sGC and regula...
Source: Free Radical Biology and Medicine - September 3, 2017 Category: Biology Authors: Kleschyov AL Tags: Free Radic Biol Med Source Type: research

Loss of Nrf2 promotes alveolar type 2 cell loss in irradiated, fibrotic lung.
Abstract The development of radiation-induced pulmonary fibrosis represents a critical clinical issue limiting delivery of therapeutic doses of radiation to non-small cell lung cancer. Identification of the cell types whose injury initiates a fibrotic response and the underlying biological factors that govern that response are needed for developing strategies that prevent or mitigate fibrosis. C57BL/6 mice (wild type, Nrf2 null, Nrf2(flox/flox), and Nrf2(Δ/Δ); SPC-Cre) were administered a thoracic dose of 12Gy and allowed to recover for 250 days. Whole slide digital and confocal microscopy imaging of H...
Source: Free Radical Biology and Medicine - September 1, 2017 Category: Biology Authors: Traver G, Mont S, Gius D, Lawson WE, Ding GX, Sekhar KR, Freeman ML Tags: Free Radic Biol Med Source Type: research

Clinical aspects and biomarkers of Alzheimer's disease in Down syndrome.
Abstract Alzheimer's disease (AD) may affect in excess of 90% of individuals with Down syndrome (DS) after age 60, due to duplication of the APP gene in trisomy of chromosome 21, with neuropathology that is comparable to Sporadic AD and Familial AD (FAD). Previous literature suggested some unique features in clinical presentation of dementia in DS (DSd), which might be due to diagnostic difficulties, or represent a real difference compared to SAD or FAD. We review current knowledge on clinical diagnosis and presentation of dementia in DS in comparison with FAD due to APP mutations and APP duplication. We suggest t...
Source: Free Radical Biology and Medicine - September 1, 2017 Category: Biology Authors: Zis P, Strydom A Tags: Free Radic Biol Med Source Type: research

Poly (I:C) impairs NO donor-induced relaxation by overexposure to NO via the NF-kappa B/iNOS pathway in rat superior mesenteric arteries.
Abstract Recent studies have suggested a link between vascular dysfunction and innate immune activation including toll-like receptors (TLRs), but the detailed mechanism remains unclear. Here we investigated whether poly (I:C) [a synthetic double-strand RNA recognized by TLR3, melanoma differentiation-associated gene 5 (MDA5), and retinoic acid-inducible gene I (RIG-I)] affected nitric oxide (NO)/cGMP-related vascular relaxation, one of the major cascades of relaxation, in rat superior mesenteric arteries. Using organ cultured arteries, we found that poly (I:C) (30 μg/ml for approximately 1day) markedly reduced ...
Source: Free Radical Biology and Medicine - September 1, 2017 Category: Biology Authors: Ando M, Matsumoto T, Taguchi K, Kobayashi T Tags: Free Radic Biol Med Source Type: research

Functional characterization of the methionine sulfoxide reductase repertoire in Trypanosoma brucei.
Abstract To combat the deleterious effects that oxidation of the sulfur atom in methionine to sulfoxide may bring, aerobic cells express repair pathways involving methionine sulfoxide reductases (MSRs) to reverse the above reaction. Here, we show that Trypanosoma brucei, the causative agent of African trypanosomiasis, expresses two distinct trypanothione-dependent MSRs that can be distinguished from each other based on sequence, sub-cellular localisation and substrate preference. One enzyme found in the parasite's cytosol, shows homology to the MSRA family of repair proteins and preferentially metabolises the S ep...
Source: Free Radical Biology and Medicine - August 30, 2017 Category: Biology Authors: Guerrero SA, Arias DG, Cabeza MS, Law MCY, D'Amico M, Kumar A, Wilkinson SR Tags: Free Radic Biol Med Source Type: research

Potential role of ferric hemoglobin in MS pathogenesis: Effects of oxidative stress and extracellular methemoglobin or its degradation products on myelin components.
Abstract There is a well-documented relationship between cerebral vasculature and multiple sclerosis (MS) lesions: abnormal accumulations of iron have been found in the walls of the dilated veins in cerebral MS plaques. The source of this iron is unknown, but could be related to the recognized phenomenon of capillary and venous hemorrhages leading to blood extravasation. In turn, hemorrhaging leading to hemolysis results in extracellular release of hemoglobin, a reactive molecule that could induce local oxidative stress, inflammation, and tissue damage. Our previous studies with a reduced form of hemoglobin (oxyHb...
Source: Free Radical Biology and Medicine - August 29, 2017 Category: Biology Authors: Bamm VV, Henein MEL, Sproul SLJ, Lanthier DK, Harauz G Tags: Free Radic Biol Med Source Type: research

Mitochondrial dysfunction in the APP/PSEN1 mouse model of Alzheimer's disease and a novel protective role for ascorbate.
This study suggests that both presence of amyloid and ascorbate deficiency can contribute to mitochondrial dysfunction, even at an early, prodromal stage of Alzheimer's disease, although occurring via different pathways. Ascorbate may, therefore, provide a useful preventative strategy against neurodegenerative disease, particularly in populations most at risk for Alzheimer's disease in which stores are often depleted through mitochondrial dysfunction and elevated oxidative stress. PMID: 28863942 [PubMed - as supplied by publisher] (Source: Free Radical Biology and Medicine)
Source: Free Radical Biology and Medicine - August 29, 2017 Category: Biology Authors: Dixit S, Fessel JP, Harrison FE Tags: Free Radic Biol Med Source Type: research

Dimercapto-1-propanesulfonic acid (DMPS) induces metaphase II mouse oocyte deterioration.
Abstract In light of the recent lead contamination of the water in Flint, Michigan and its potential adverse outcomes, much research and media attention has turned towards the safety profile of commonly used chelators. Dimercapto-1-propanesulfonic acid (DMPS) typically used in the treatment of lead, mercury and arsenic poisoning also displays a high affinity towards transition metals such as zinc and copper, essential for biological functioning. It is given in series of dosages (0.2-0.4g/day) over a long period, and has the ability to enter cells. In this work, we investigated the mechanism through which increasin...
Source: Free Radical Biology and Medicine - August 24, 2017 Category: Biology Authors: Aldhaheri SR, Jeelani R, Kohan-Ghadr HR, Khan SN, Mikhael S, Washington C, Morris RT, Abu-Soud HM Tags: Free Radic Biol Med Source Type: research

Extracellular Superoxide Dismutase and its Role in Cancer.
Abstract Reactive oxygen species (ROS) are increasingly recognized as critical determinants of cellular signaling and a strict balance of ROS levels must be maintained to ensure proper cellular function and survival. Notably, ROS is increased in cancer cells. The superoxide dismutase family plays an essential physiological role in mitigating deleterious effects of ROS. Due to the compartmentalization of ROS signaling, EcSOD, the only superoxide dismutase in the extracellular space, has unique characteristics and functions in cellular signal transduction. In comparison to the other two intracellular SODs, EcSOD is ...
Source: Free Radical Biology and Medicine - August 23, 2017 Category: Biology Authors: Griess B, Tom E, Domann F, Teoh-Fitzgerald M Tags: Free Radic Biol Med Source Type: research

Elimination of dysfunctional mitochondria through mitophagy suppresses Benzo[a]pyrene-induced apoptosis.
In this study, we examined the molecular mechanism of mitophagy induction with benzo[a]pyrene (B[a]P), a ubiquitous polycyclic aromatic hydrocarbon, which acts as a prosurvival response against apoptotic cell death. Our study showed that B[a]P displayed higher cytotoxicity in autophagy-deficient HaCaT cells as compared to control. Further, we showed that B[a]P triggered the Beclin-1-dependent autophagy through the mamalian target of rapamycin (mTOR)/AMP-activated protein kinase (AMPK) pathway. Moreover, our study indicated that the B[a]P-induced autophagy was initiated through the activation of cytochrome P450 1B1 (CYP1B1)...
Source: Free Radical Biology and Medicine - August 23, 2017 Category: Biology Authors: Das DN, Naik PP, Mukhopadhyay S, Panda PK, Sinha N, Meher BR, Bhutia SK Tags: Free Radic Biol Med Source Type: research

Endogenous, Regulatory Cysteine Sulfenylation of ERK Kinases in Response to Proliferative Signals.
We report that ERK is actively and directly oxidized by signal-generated H2O2 during proliferative signaling, and that ERK oxidation occurs downstream of a variety of receptor classes tested in four cell lines. Furthermore, within the tested cell lines and proliferative signals, we observed that both activation loop-phosphorylated and non-phosphorylated ERK undergo sulfenylation in cells and that dynamics of ERK sulfenylation is dependent on the cell growth conditions prior to stimulation. We also tested the effect of endogenous ERK oxidation on kinase activity and report that phosphotransfer reactions are reversibly inhib...
Source: Free Radical Biology and Medicine - August 23, 2017 Category: Biology Authors: Keyes JD, Parsonage D, Yammani RD, Rogers LAC, Kesty C, Furdui CM, Nelson KJ, Poole LB Tags: Free Radic Biol Med Source Type: research

Epidemiology of Estrogen and Dementia in Women with Down Syndrome.
Abstract Several lines of investigation have shown a protective role for estrogen in Alzheimer's disease through a number of biological actions. This review examines studies of the role of estrogen-related factors in age at onset and risk for Alzheimer's disease in women with Down syndrome, a population at high risk for early onset of dementia. The studies are consistent in showing that early age at menopause and that low levels of endogenous bioavailable estradiol in postmenopausal women with Down syndrome are associated with earlier age at onset and overall risk for dementia. Polymorphisms in genes associated wi...
Source: Free Radical Biology and Medicine - August 23, 2017 Category: Biology Authors: Schupf N, Lee JH, Pang D, Zigman WB, Tycko B, Krinsky-McHale S, Silverman W Tags: Free Radic Biol Med Source Type: research

Hydrogen sulfide-producing cystathionine γ-lyase is critical in the progression of kidney fibrosis.
Hydrogen sulfide-producing cystathionine γ-lyase is critical in the progression of kidney fibrosis. Free Radic Biol Med. 2017 Aug 22;: Authors: Han SJ, Noh MR, Jung JM, Ishii I, Yoo J, Kim JI, Park KM Abstract Cystathionine γ-lyase (CSE), the last key enzyme of the transsulfuration pathway, is involved in the production of hydrogen sulfide (H2S) and glutathione (GSH), which regulate redox balance and act as important antioxidant molecules. Impairment of the H2S- and GSH-mediated antioxidant system is associated with the progression of chronic kidney disease (CKD), characterized by kidney f...
Source: Free Radical Biology and Medicine - August 22, 2017 Category: Biology Authors: Han SJ, Noh MR, Jung JM, Ishii I, Yoo J, Kim JI, Park KM Tags: Free Radic Biol Med Source Type: research

Extracellular reactive oxygen species are generated by a plasma membrane oxidative phosphorylation system.
Abstract Although the oxidative phosphorylation (OXPHOS) system has been found in mitochondria and the plasma membrane of various mammalian cell lines, understanding the physiological functions of the plasma membrane OXPHOS system is challenging. Here, we demonstrated that OXPHOS I, II, III, IV and V subunits were expressed in the plasma membrane of HepG2 cells and primary mouse hepatocytes, as determined by non-permeabilized immunofluorescence, total internal reflection fluorescence (TIRF) microscopy, cell surface-biotin labeling and plasma membrane and lipid raft isolation. Next, we demonstrated that NADH admini...
Source: Free Radical Biology and Medicine - August 22, 2017 Category: Biology Authors: Lee H, Kim BW, Lee JW, Hong J, Lee JW, Kim HL, Lee JS, Ko YG Tags: Free Radic Biol Med Source Type: research

Mitochondria as Pharmacological Targets in Down syndrome.
Abstract Mitochondria play a pivotal role in cellular energy-generating processes and are considered master regulators of cell life and death fate. Mitochondrial function integrates signalling networks in several metabolic pathways controlling neurogenesis and neuroplasticity. Indeed, dysfunctional mitochondria and mitochondrial-dependent activation of intracellular stress cascades are critical initiating events in many human neurodegenerative or neurodevelopmental diseases including Down syndrome (DS). It is well established that trisomy of human chromosome 21 can cause DS. DS is associated with neurodevelopmenta...
Source: Free Radical Biology and Medicine - August 21, 2017 Category: Biology Authors: Valenti D, Braidy N, De Rasmo D, Signorile A, Rossi L, Georgiev Atanasov A, Volpicella M, Henrion-Caude A, Mohammad Nabavi S, Anna Vacca R Tags: Free Radic Biol Med Source Type: research

Ellagic Acid Antagonizes Bnip3 -Mediated Mitochondrial Injury and Necrotic Cell Death of Cardiac Myocytes.
Abstract The Bcl-2 protein Bnip3 is crucial for provoking oxidative injury to mitochondria following anthracycline treatment or ischemia-reperfusion inury. Herein, we investigate the effects of the polyphenolic compound ellagic acid (EA) on Bnip3 mediated mitochondrial injury and necrotic cell death in cardiac myocytes. In contrast to vehicle treated cardiomyocytes, Bnip3 was highly enriched in mitochondrial fractions of cardiac myocytes treated with the anthracycline doxorubicin or in cells subjected to hypoxia (HPX). Mitochondrial associated Bnip3 was accompanied by mPTP opening and loss of ∆Ψm. The dynami...
Source: Free Radical Biology and Medicine - August 21, 2017 Category: Biology Authors: Dhingra A, Jayas R, Afshar P, Guberman M, Maddaford G, Gerstein J, Lieberman B, Nepon H, Margulets V, Dhingra R, Kirshenbaum LA Tags: Free Radic Biol Med Source Type: research

Advanced glycation end products receptor RAGE controls myocardial dysfunction and oxidative stress in high-fat fed mice by sustaining mitochondrial dynamics and autophagy-lysosome pathway.
In conclusion, modulation of RAGE pathway may improve mitochondrial damage and myocardial dysfunction in HFD mice. Attenuation of cardiac oxidative stress and maintenance of healthy mitochondria population ensuring adequate energy supply may be involved in myocardial protection against HFD. PMID: 28826719 [PubMed - as supplied by publisher] (Source: Free Radical Biology and Medicine)
Source: Free Radical Biology and Medicine - August 18, 2017 Category: Biology Authors: Yu Y, Wang L, Delguste F, Durand A, Guilbaud A, Rousselin C, Schmidt AM, Tessier F, Boulanger E, Neviere R Tags: Free Radic Biol Med Source Type: research

G6PD plays a neuroprotective role in brain ischemia through promoting pentose phosphate pathway.
Abstract TIGAR-regulated pentose phosphate pathway (PPP) plays a critical role in the neuronal survival during cerebral ischemia/reperfusion. Glucose-6-phosphate dehydrogenase (G6PD) is a rate-limiting enzyme in PPP and thus, we hypothesized that it plays an essential role in anti-oxidative defense through producing NADPH. The present study investigated the regulation and the role of G6PD in ischemia/reperfusion-induced neuronal injury with in vivo and in vitro models of ischemic stroke. The results showed that the levels of G6PD mRNA and protein were increased after ischemia/reperfusion. In vivo, lentivirus-media...
Source: Free Radical Biology and Medicine - August 17, 2017 Category: Biology Authors: Cao L, Zhang D, Chen J, Qin YY, Sheng R, Feng X, Chen Z, Ding Y, Li M, Qin ZH Tags: Free Radic Biol Med Source Type: research

Systematical exploration of transcription factors in cardiomyocytes against hydrogen peroxide-induced oxidative stress by Danhong injection.
In this study, a new method, concatenated tandem array of consensus transcription factor response elements (catTFREs), and an Illumina-based RNA-seq technology were integrated and then combined with a network pharmacology strategy to systematically investigate the role of TFs in hydrogen peroxide (H2O2)-induced oxidative stress in cardiomyocytes; the damage was then rescued by Danhong injection (DHI), a Chinese standardized product approved for cardiovascular diseases treatment. The overall gene expression revealed cell apoptosis and DNA repair were vital for cardiomyocytes in resisting oxidative stress. By comprehensively...
Source: Free Radical Biology and Medicine - August 16, 2017 Category: Biology Authors: Zhang J, Guo F, Wei J, Xian M, Tang S, Zhao Y, Liu M, Song L, Geng Y, Yang H, Ding C, Huang L Tags: Free Radic Biol Med Source Type: research

NADPH oxidases as drug targets and biomarkers in neurodegenerative diseases: what is the evidence?
Abstract Neurodegenerative disease are frequently characterized by microglia activation and/or leukocyte infiltration in the parenchyma of the central nervous system and at the molecular level by increased oxidative modifications of proteins, lipids and nucleic acids. NADPH oxidases (NOX) emerged as a novel promising class of pharmacological targets for the treatment of neurodegeneration due to their role in oxidant generation and presumably in regulating microglia activation. The unique function of NOX is the generation of superoxide anion (O2(•-)) and hydrogen peroxide (H2O2). However in the context of neur...
Source: Free Radical Biology and Medicine - August 12, 2017 Category: Biology Authors: Sorce S, Stocker R, Seredenina T, Holmdahl R, Aguzzi A, Chio A, Depaulis A, Heitz F, Olofsson P, Olsson T, Duveau V, Sanoudou D, Skosgater S, Vlahou A, Wasquel D, Krause KH, Jaquet V Tags: Free Radic Biol Med Source Type: research

Bcl-xL knockout attenuates mitochondrial respiration and causes oxidative stress that is compensated by pentose phosphate pathway activity.
r A Abstract Bcl-xL is an anti-apoptotic protein that localizes to the outer mitochondrial membrane and influences mitochondrial bioenergetics by controlling Ca(2+) influx into mitochondria. Here, we analyzed the effect of mitochondrial Bcl-xL on mitochondrial shape and function in knockout (KO), wildtype and rescued mouse embryonic fibroblast cell lines. Mitochondria of KO cells were more fragmented, exhibited a reduced ATP concentration, and reduced oxidative phosphorylation (OXPHOS) suggesting an increased importance of ATP generation by other means. Under steady-state conditions, acidification of the growth me...
Source: Free Radical Biology and Medicine - August 11, 2017 Category: Biology Authors: Pfeiffer A, Schneider J, Bueno D, Dolga A, Voss TD, Lewerenz J, Wüllner V, Methner A Tags: Free Radic Biol Med Source Type: research

mTOR IN DOWN SYNDROME: ROLE in A ß and TAU NEUROPATHOLOGY and TRANSITION to ALZHEIMER DISEASE-LIKE DEMENTIA.
mTOR IN DOWN SYNDROME: ROLE in Aß and TAU NEUROPATHOLOGY and TRANSITION to ALZHEIMER DISEASE-LIKE DEMENTIA. Free Radic Biol Med. 2017 Aug 11;: Authors: Di Domenico F, Tramutola A, Foppoli C, Head E, Perluigi M, Butterfield DA Abstract The mammalian target of rapamycin (mTOR) is a serine/threonine protein kinase involved in the regulation of protein synthesis and degradation, longevity and cytoskeletal formation. The mTOR pathway represents a key growth and survival pathway involved in several diseases such as cancer, obesity, cardiovascular disease and neurodegenerative diseases. Numerous studie...
Source: Free Radical Biology and Medicine - August 11, 2017 Category: Biology Authors: Di Domenico F, Tramutola A, Foppoli C, Head E, Perluigi M, Butterfield DA Tags: Free Radic Biol Med Source Type: research

Assessment of glutathione/glutathione disulphide ratio and S-glutathionylated proteins in human blood, solid tissues, and cultured cells.
Abstract Glutathione (GSH) is the major non-protein thiol in humans and other mammals, which is present in millimolar concentrations within cells, but at much lower concentrations in the blood plasma. GSH and GSH-related enzymes act both to prevent oxidative damage and to detoxify electrophiles. Under oxidative stress, two GSH molecules become linked by a disulphide bridge to form glutathione disulphide (GSSG). Therefore, assessment of the GSH/GSSG ratio may provide an estimation of cellular redox metabolism. Current evidence resulting from studies in human blood, solid tissues, and cultured cells suggests that GS...
Source: Free Radical Biology and Medicine - August 11, 2017 Category: Biology Authors: Giustarini D, Colombo G, Lisa Garavaglia M, Astori E, Marcello Portinaro N, Reggiani F, Badalamenti S, Maria Aloisi A, Santucci A, Rossi R, Milzani A, Dalle-Donne I Tags: Free Radic Biol Med Source Type: research

Oxidant species are involved in T/B-mediated ERK1/2 phosphorylation that activates p53-p21 axis to promote KSHV lytic cycle in PEL cells.
Abstract KSHV is a gammaherpesvirus strongly associated to human cancers such as Primary Effusion Lymphoma (PEL) and Kaposi's Sarcoma. The naturally virus-infected tumor cells usually display latent infection since a minority of cells undergoes spontaneous viral replication. The lytic cycle can be induced in vitro upon appropriate stimuli such as TPA (T), alone or in combination with butyrate (B), (T/B). In previous studies, Protein Kinase C (PKC) δ, Extracellular Signal-regulated Kinase1/2 (ERK1/2) and p53-p21 axis have been separately reported to play a role in KSHV reactivation from latency. Here, we foun...
Source: Free Radical Biology and Medicine - August 8, 2017 Category: Biology Authors: Gonnella R, Yadav S, Montani MSG, Granato M, Santarelli R, Garufi A, D'Orazi G, Faggioni A, Cirone M Tags: Free Radic Biol Med Source Type: research

Peroxiredoxin-2 plays a pivotal role as multimodal cytoprotector in the early phase of pulmonary hypertension.
PEROXIREDOXIN-2 PLAYS A PIVOTAL ROLE AS MULTIMODAL CYTOPROTECTOR IN THE EARLY PHASE OF PULMONARY HYPERTENSION. Free Radic Biol Med. 2017 Aug 08;: Authors: Federti E, Matte' A, Ghigo A, Andolfo I, James C, Siciliano A, Leboeuf C, Janin A, Manna F, Choi SY, Iolascon A, Beneduce E, Melisi D, Kim DW, Levi S, De Franceschi L Abstract Pulmonary-artery-hypertension (PAH) is a life-threatening and highly invalidating chronic disorder. Chronic oxidation contributes to lung damage and disease progression. Peroxiredoxin-2 (Prx2) is a typical 2-cysteine (Cys) peroxiredoxin but its role on lung homestasis is yet t...
Source: Free Radical Biology and Medicine - August 8, 2017 Category: Biology Authors: Federti E, Matte' A, Ghigo A, Andolfo I, James C, Siciliano A, Leboeuf C, Janin A, Manna F, Choi SY, Iolascon A, Beneduce E, Melisi D, Kim DW, Levi S, De Franceschi L Tags: Free Radic Biol Med Source Type: research

Mdivi-1 ameliorates early brain injury after subarachnoid hemorrhage via the suppression of inflammation-related blood-brain barrier disruption and endoplasmic reticulum stress-based apoptosis.
In conclusion, these data implied that excessive mitochondrial fission might inhibit mitochondrial complex I to become a cause of oxidative stress in SAH, and the inhibition of Drp1 by Mdivi-1 attenuated early brain injury after SAH probably via the suppression of inflammation-related blood-brain barrier disruption and endoplasmic reticulum stress-based apoptosis. PMID: 28790012 [PubMed - as supplied by publisher] (Source: Free Radical Biology and Medicine)
Source: Free Radical Biology and Medicine - August 5, 2017 Category: Biology Authors: Fan LF, He PY, Peng YC, Du QH, Ma YJ, Jin JX, Xu HZ, Li JR, Wang ZJ, Cao SL, Li T, Yan F, Gu C, Wang L, Chen G Tags: Free Radic Biol Med Source Type: research

Chronic vitamin E deficiency impairs cognitive function in adult zebrafish via dysregulation of brain lipids and energy metabolism.
Abstract Zebrafish (Danio rerio) are a recognized model for studying the pathogenesis of cognitive deficits and the mechanisms underlying behavioral impairments, including the consequences of increased oxidative stress within the brain. The lipophilic antioxidant vitamin E (α-tocopherol; VitE) has an established role in neurological health and cognitive function, but the biological rationale for this action remains unknown. In the present study, we investigated behavioral perturbations due to chronic VitE deficiency in adult zebrafish fed from 45 days to 18-months of age diets that were either VitE-deficient...
Source: Free Radical Biology and Medicine - August 5, 2017 Category: Biology Authors: McDougall M, Choi J, Magnusson K, Truong L, Tanguay R, Traber MG Tags: Free Radic Biol Med Source Type: research

DMAPT inhibits NF- κB activity and increases sensitivity of prostate cancer cells to X-rays in vitro and in tumor xenografts in vivo.
DMAPT inhibits NF-κB activity and increases sensitivity of prostate cancer cells to X-rays in vitro and in tumor xenografts in vivo. Free Radic Biol Med. 2017 Aug 03;: Authors: Mendonca MS, Turchan WT, Alpuche ME, Watson CN, Estabrook NC, Chin-Sinex H, Shapiro JB, Imasuen-Williams IE, Rangel G, Gilley DP, Huda N, Crooks PA, Shapiro RH Abstract Constitutive activation of the pro-survival transcription factor NF-κB has been associated with resistance to both chemotherapy and radiation therapy in many human cancers, including prostate cancer. Our lab and others have demonstrated that the natu...
Source: Free Radical Biology and Medicine - August 3, 2017 Category: Biology Authors: Mendonca MS, Turchan WT, Alpuche ME, Watson CN, Estabrook NC, Chin-Sinex H, Shapiro JB, Imasuen-Williams IE, Rangel G, Gilley DP, Huda N, Crooks PA, Shapiro RH Tags: Free Radic Biol Med Source Type: research

Importance of NADPH oxidase-mediated redox signaling in the detrimental effect of CRP on pancreatic insulin secretion.
Abstract Elevations in C-reactive protein (CRP) levels are positively correlated with the progress of type 2 diabetes mellitus. However, the effect of CRP on pancreatic insulin secretion is unknown. Here, we showed that purified human CRP impaired insulin secretion in isolated mouse islets and NIT-1 insulin-secreting cells in dose- and time-dependent manners. CRP increased NADPH oxidase-mediated ROS (reactive oxygen species) production, which simultaneously promoted the production of nitrotyrosine (an indicator of RNS, reactive nitrogen species) and TNFα, to diminish cell viability, insulin secretion in isle...
Source: Free Radical Biology and Medicine - August 1, 2017 Category: Biology Authors: Chan PC, Wang YC, Chen YL, Hsu WN, Tian YF, Hsieh PS Tags: Free Radic Biol Med Source Type: research

Intermittent hypoxia-induced cardiomyopathy and its prevention by Nrf2 and metallothionein.
We reported the prevention of acute and chronic IH-induced cardiac damage by selective cardiac overexpression of metallothionein (MT). Herein we defined that MT-mediated protection from IH-cardiomyopathy is via activation of nuclear factor erythroid 2-related factor 2 (Nrf2), a critical redox-balance controller in the body. For this, mice were exposed to IH for 3 days (acute) or 4 or 8 weeks (chronic). Cardiac Nrf2 and MT expression in response to IH were significantly increased acutely yet decreased chronically. Interestingly, cardiac overexpression (Nrf2-TG) or global deletion of the Nrf2 gene (Nrf2-KO) made mice highly ...
Source: Free Radical Biology and Medicine - August 1, 2017 Category: Biology Authors: Zhou S, Yin X, Jin J, Tan Y, Conklin DJ, Xin Y, Zhang Z, Sun W, Cui T, Cai J, Zheng Y, Cai L Tags: Free Radic Biol Med Source Type: research

Antioxidant defense in quiescent cells determines selectivity of electron transport chain inhibition-induced cell death.
Abstract Mitochondrial electron transport chain (ETC) targeting shows a great promise in cancer therapy. It is particularly effective in tumors with high ETC activity where ETC-derived reactive oxygen species (ROS) are efficiently induced. Why modern ETC-targeted compounds are tolerated on the organismal level remains unclear. As most somatic cells are in non-proliferative state, the features associated with the ETC in quiescence could account for some of the specificity observed. Here we report that quiescent cells, despite increased utilization of the ETC and enhanced supercomplex assembly, are less susceptible ...
Source: Free Radical Biology and Medicine - July 31, 2017 Category: Biology Authors: Blecha J, Novais SM, Rohlenova K, Novotna E, Lettlova S, Schmitt S, Zischka H, Neuzil J, Rohlena J Tags: Free Radic Biol Med Source Type: research

Redox Regulation of the Tumor Suppressor PTEN by the Thioredoxin System and Cumene Hydroperoxide.
In this study, we investigated the effect of CuHP on the redox state of PTEN in HeLa cells. In addition, the intracellular reducing system of oxidized PTEN was analyzed by using a biochemical approach and the effect of CuHP on this reducing system was also analyzed. While PTEN oxidized by hydrogen peroxide is progressively converted to its reduced form, PTEN was irreversibly oxidized by exposure to cumene hydroperoxide (CuHP) in HeLa cells. A combination of protein fractionation and mass analysis identified the reducing system of PTEN comprised of NADPH, thioredoxin reductase (TrxR) and thioredoxin (Trx). Although CuHP-med...
Source: Free Radical Biology and Medicine - July 31, 2017 Category: Biology Authors: Han SJ, Zhang Y, Kim I, Chay KO, Yoon HJ, Jang DI, Park J, Woo HA, Park I, Lee SR Tags: Free Radic Biol Med Source Type: research

Euphorbia factor L1 inhibits osteoclastogenesis by regulating cellular redox status and induces Fas-mediated apoptosis in osteoclast.
This study shows that euphorbia factor L1 (EFL1), a diterpenoid isolated from Euphorbia lathyris, inhibited osteoclastogenesis and induced osteoclast apoptosis. EFL1 suppressed osteoclast formation and bone resorption at both initial and terminal differentiation stages. EFL1 inhibited receptor activator of NF-κB ligand (RANKL)-induced NFATc1 induction with attenuated NF-κB activation and c-Fos expression. EFL1 decreased the level of reactive oxygen species by scavenging them or activating Nrf2, and inhibited PGC-1β that regulates mitochondria biogenesis. In addition, EFL1 induced apoptosis in differentiate...
Source: Free Radical Biology and Medicine - July 31, 2017 Category: Biology Authors: Hong SE, Lee J, Seo DH, In Lee H, Ri Park D, Lee GR, Jo YJ, Kim N, Kwon M, Shon H, Kyoung Seo E, Kim HS, Young Lee S, Jeong W Tags: Free Radic Biol Med Source Type: research