Joe mcCord

For the past 40 years or so, oxidative stress has been increasingly recognized as a contributing factor in aging and in various forms of pathophysiology generally associated with aging. Our view of oxidative stress has been largely "superoxide-centric", as we focused on the pathological sources of this oxygen-derived free radical and the types of molecular havoc it can wreak, as well as on the protection provided by the antioxidant enzymes, especially the superoxide dismutases, catalases, and glutathione peroxidases...

Hydroxychalcones are naturally occurring compounds that continue to attract considerable interest because of their anti-inflammatory and antiangiogenic properties. They have been reported to inhibit the synthesis of the inducible nitric oxide synthase and to induce the expression of heme oxygenase-1. This study examines the mechanisms by which 2',5'-dihydroxychalcone (2',5'-DHC) induces an increase in cellular glutathione (GSH) levels using a cell line stably expressing a luciferase reporter gene driven by antioxidant-response elements (MCF-7/AREc32)...

Human saphenous veins (HSVs) are widely used for bypass grafts despite their relatively low long-term patency. To evaluate the role of reactive oxygen species (ROS) signaling in intima hyperplasia (IH), an early stage pathology of vein-graft disease, and to explore the potential therapeutic effects of up-regulating endogenous antioxidant enzymes, we studied segments of HSV cultured ex vivo in an established ex vivo model of HSV IH. Results showed that HSV cultured ex vivo exhibit an ~3-fold increase in proliferation and ~3...

Delivery of recombinant superoxide dismutase to the lung is limited by its short half-life and poor tissue penetration. We hypothesized that a chimeric protein, SOD2/3, containing the enzymatic domain of manganese superoxide dismutase (SOD2) and the heparan-binding domain of extracellular superoxide dismutase (SOD3), would allow for the delivery of more sustained lung and pulmonary vascular antioxidant activity compared to SOD2. We administered SOD2/3 to rats by intratracheal (i.t.), intraperitoneal (i.p.), or intravenous (i...

Therapeutic options for Duchenne muscular dystrophy (DMD), the most common and lethal neuromuscular disorder in children, remain elusive. Oxidative damage is implicated as a pertinent factor involved in its pathogenesis. Protandim((R)) is an over-the-counter supplement with the ability to induce antioxidant enzymes. In this study we investigated whether Protandim((R)) provided benefit using surrogate markers and functional measures in the dystrophin-deficient (mdx)mouse model of DMD. Male 3-week-old mdx mice were randomized into two treatment groups: control (receiving standard rodent chow) and Protandim((R))-supplemented standard rodent chow...

Protandim, a well defined dietary combination of 5 well-established medicinal plants, is known to induce endogenous antioxidant enzymes, such as manganese superoxide dismutase (MnSOD). Our previous studies have shown through the induction of various antioxidant enzymes, products of oxidative damage can be decreased. In addition, we have shown that tumor multiplicity and incidence can be decreased through the dietary administration of Protandim in the two-stage skin carcinogenesis mouse model. It has been demonstrated that cell proliferation is accommodated by cell death during DMBA/TPA treatment in the two-stage skin carcinogenesis model...

Dr. Irwin Fridovich (Ph.D., 1955) is recognized here as a Redox Pioneer because as first/last author he has published at least 1 paper on antioxidant/redox biology that has been cited over 1000 times and has published at least 10 papers each cited over 100 times. In collaboration with his graduate student, Joe McCord, Dr. Fridovich discovered the activity of superoxide dismutase (SOD). Subsequently, he and his colleagues demonstrated that the enzyme is ubiquitous among aerobic biota and comprises a critical defense against oxidative stress...

Mitochondrial free radical formation has been implicated as a potential mechanism underlying degenerative senescence, although human data are lacking. Therefore, the present study was designed to examine if resting and exercise-induced intramuscular free radical-mediated lipid peroxidation is indeed increased across the spectrum of sedentary aging. Biopsies were obtained from the vastus lateralis in six young (26 + or - 6 yr) and six aged (71 + or - 6 yr) sedentary males at rest and after maximal knee extensor exercise...

We previously described a coding mutation (L60F) in the mitochondrial superoxide dismutase (SOD2) gene of the human T cell leukemia-derived cell line Jurkat. In cell extracts the L60F mutant enzyme showed unusual inhibition by thiol reagents not seen in wild-type enzyme. Here we compare the properties of purified recombinant L60F SOD2 with a previously described SOD2 mutant, I58T. Both mutant proteins display a weakened dimer-dimer interaction and thermal instability at 55 degrees C. Both I58T and L60F lose activity at 37 degrees C in the presence of 5 mM N-ethylmaleimide, whereas the wild-type SOD2 does not...

BACKGROUND: The most important determinant of longevity in pulmonary arterial hypertension is right ventricular (RV) function, but in contrast to experimental work elucidating the pathobiology of left ventricular failure, there is a paucity of data on the cellular and molecular mechanisms of RV failure. METHODS AND RESULTS: A mechanical animal model of chronic progressive RV pressure overload (pulmonary artery banding, not associated with structural alterations of the lung circulation) was compared with an established model of angioproliferative pulmonary hypertension associated with fatal RV failure...

This study examined whether hypoxia causes free radical-mediated disruption of the blood-brain barrier (BBB) and impaired cerebral oxidative metabolism and whether this has any bearing on neurological symptoms ascribed to acute mountain sickness (AMS). Ten men provided internal jugular vein and radial artery blood samples during normoxia and 9-h passive exposure to hypoxia (12.9% O(2)). Cerebral blood flow was determined by the Kety-Schmidt technique with net exchange calculated by the Fick principle. AMS and headache were determined with clinically validated questionnaires...

There is growing evidence of the correlation between cancer and reactive oxygen species (ROS), especially superoxide. Low expression levels of the Mn-superoxide dismutase (SOD2) enzyme have been reported in cancer patients. Genetic variation in the regulatory regions of the SOD2 gene may increase the risk of cancer. We identified a genetic variation (G1677T, rs2Y758Y339) in the vicinity of the enhancer region located in intron 2 of the SOD2 gene that creates a potential glucocorticoid responsive element, and developed an assay to screen DNA samples of 220 individuals (73 control, 59 prostate cancer survival individuals and 88 lung cancer biopsies)...

Oxidative stress is an important contributor to cancer development. Consistent with that, antioxidant enzymes have been demonstrated to suppress tumorigenesis when being elevated both in vitro and in vivo, making induction of these enzymes a more potent approach for cancer prevention. Protandim, a well-defined combination of widely studied medicinal plants, has been shown to induce superoxide dismutase (SOD) and catalase activities and reduce superoxide generation and lipid peroxidation in healthy human subjects...

Acute hypoxia causes pulmonary vascular leak and is involved in the pathogenesis of pulmonary edema associated with inflammation, acute altitude exposure, and other critical illnesses. Reactive oxygen species, HIF-1, and VEGF have all been implicated in various hypoxic pathologies, yet the ROS-HIF-1-VEGF pathway in pulmonary vascular leak has not been defined. We hypothesized that the ROS-HIF-1-VEGF pathway has an important role in producing hypoxia-induced pulmonary vascular leak. Human pulmonary artery endothelial cell (HPAEC) monolayers were exposed to either normoxia (21% O(2)) or acute hypoxia (3% O(2)) for 24 h and monolayer permeability and H(2)O(2), nuclear HIF-1alpha, and cytosolic VEGF levels were determined...

BACKGROUND: Mild oxidative stress induces the cells to proliferate. On the other hand, too much oxidative stress may cause cells to die or suffer irreversible damage. Cancer and beta-cells destruction on diabetes can illustrate the paradoxical roles of superoxide in the physiological cellular responses. METHODS: The activation of resting human peripheral blood lymphocytes (HPBL) was done using different mitogens such as phytohemagglutinin (PHA), concanavalin A (ConA), and phorbol ester (PMA), as well the superoxide producing system, paraquat...

Protandim is an antioxidant supplement that consists of five ingredients, namely, ashwagandha, bacopa extract, green tea extract, silymarin, and curcumin, each with known therapeutic properties. Protandim was formulated with the objective of combining multiple phytochemicals at low nontoxic doses to gain synergy among them. A recent clinical study demonstrated the in vivo antioxidant effects of Protandim (S.K. Nelson et al., 2006, Free Radic. Biol. Med. 40, 341-347). The objective of the present study was to determine if the components of Protandim induce heme oxygenase-1 (HO-1) in a synergistic manner in cultured MIN6 cells, a mouse beta-cell line, and in SK-N-MC cells, a human neuroblastoma cell line...

Cellular metabolism generates the cytotoxic superoxide free radical, O(2).(-), and a family of enzymes called superoxide dismutases (SOD) protects us from O(2).(-) by catalyzing its conversion to O(2) and H(2)O(2). Superoxide production increases in a wide variety of pathological states, especially those involving inflammation or ischemic injury. Most of the literature has described systems wherein added or over expressed SOD produced beneficial effects, yet in some circumstances SOD provided no benefit, or was clearly detrimental, exacerbating cell injury or death...

The evolution and development of currently known organisms, comprised their change and adaptation from the reducing atmosphere to an oxidizing one. The adaptive changes show that some processes were developed to take advantage of the oxidizing atmosphere efficiently. The most important adaptive change was the efficiency in the energy production of aerobic organisms. Some toxic wastes of this process, known as reactive oxygen species, have deleterious functions when modifying and damaging structural and metabolic components of the cells...

The present study determined if acute exercise increased free radical formation in human skeletal muscle. Vastus lateralis biopsies were obtained in a randomized balanced order from six males at rest and following single-leg knee extensor exercise performed for 2 min at 50% of maximal work rate (WR(MAX)) and 3 min at 100% WR(MAX). EPR spectroscopy revealed an exercise-induced increase in mitochondrial ubisemiquinone (UQ*-) [0.167 +/- 0.055 vs. rest: 0.106 +/- 0.047 arbitrary units (AU)/g total protein (TP), P < 0...

Reactive oxygen species (ROS) have been implicated in the cellular membrane damage and postoperative morbidity associated with obligatory ischemia-reperfusion (I-R) during vascular surgery. Thus, a clinical study was undertaken to evaluate the effects of ascorbate prophylaxis on ROS exchange kinetics in 22 patients scheduled for elective abdominal aortic aneurysm (AAA) or infra-inguinal bypass (IIB) repair. Patients were assigned double-blind to receive intravenous sodium ascorbate (2 g vitamin C, n=10) or placebo (0...