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Papers by Joe McCord

The American Journal of Physiology, Jul 1, 1984

Oxygen-derived free radicals have been proposed as general mediators of tissue injury in a variet... more Oxygen-derived free radicals have been proposed as general mediators of tissue injury in a variety of disease states. Recent interest has focused on the possibility that free radicals may be involved in ischemic myocardial damage. However, the exact types of damage that result from myocardial exposure to free radicals remains to be established. The purpose of this study was to evaluate the effects of superoxide and hydroxyl radicals on myocardial structure and function in an isolated perfused rabbit interventricular septal preparation. Superoxide was generated by adding purine (2.3 mM) and xanthine oxidase (0.01 U/ml) to the physiological solutions perfusing the septa. Hydroxyl radical generation was catalyzed by the addition of 2.4 microM Fe3+-loaded transferrin to the system. Exposure of normal septa to superoxide-generating solutions resulted in the development of structural alterations in the vascular endothelium including the development of vacuoles. Membranous cellular debris was evident in the extracellular space and within the vessels. Cardiac myocytes showed evidence of mild alterations. Exposure of septa to solutions capable of generating hydroxyl radicals resulted in more extensive and severe damage. Vascular endothelial cells showed evidence of vacuoles or blebs and edema. Severe swelling of mitochondria was evident in cardiac myocytes and vascular endothelial cells. In addition, myocytes often showed blebbing of the basement membrane. Normal septa exposed to superoxide showed no significant decrease in developed tension, whereas hydroxyl radical exposure resulted in a significant decrease in myocardial function.(ABSTRACT TRUNCATED AT 250 WORDS)

The Faseb Journal, Apr 1, 2013

ABSTRACT Consumption of a high salt (HS) diet results in vascular oxidant stress and impairs endo... more ABSTRACT Consumption of a high salt (HS) diet results in vascular oxidant stress and impairs endothelium-dependent relaxation in a variety of human and experimental models. Nuclear factor erythroid-2-related factor 2 (Nrf2) is a transcription factor that induces the expression of many critical antioxidant genes. We measured protein expression of Nrf2 and its cytosolic inhibitor, kelch-like ECH-associated protein 1 (Keap1), in mesenteric and cerebral arterial homogenates from Sprague-Dawley (SD) rats fed HS (4% NaCl), low salt (LS), or HS with low dose angiotensin II (ANG II) infusion to restore normal plasma ANG II levels. While Nrf2 expression was similar between groups, Keap1 expression was significantly lower in ANG II-infused rats (p < 0.05). The Nrf2:Keap1 ratio normalized to LS was significantly increased in both mesenteric (LS = 100.00% ± 19.76; HS = 176.34% ± 29.98; HS + ANG II = 561.44% ± 210.39) and cerebral (LS = 100.00% ± 16.21; HS = 181.67% ± 69.31; HS + ANG II = 677.55% ± 172.38) arterial beds. The dietary supplement Protandim, shown to induce Nrf2 expression, improved endothelium-dependent relaxation to acetylcholine in salt-fed SD rats (HS = 0.50 μm ± 0.96; HS + Protandim = 6.67 μm ± 1.28; p = 0.008) and hamsters (HS = 1.33 μm ± 0.52; HS + Protandim = 5.60 μm ± 0.68; p < 0.001 ). Together, these data suggest a functional role for the Nrf2 antioxidant defense system in preventing salt-induced vascular dysfunction.

Diabetologia, 1984

In studies to evaluate possible inhibitors of the Bcell toxin, streptozotocin, the superoxide sca... more In studies to evaluate possible inhibitors of the Bcell toxin, streptozotocin, the superoxide scavenger, superoxide dismutase, did not prevent or reduce the toxic effects of streptozotocin as determined by loss of insulin secretion from rat pancreatic B cells in monolayer culture. However, 1,l-dimethyl urea, a scavenger of the hydroxyl radical, did afford significant protection. Both scavengers diminished the cytotoxic effects of alloxan. The inhibitors of poly (ADP-ribose) synthetase, 3-aminobenzamide and nicotinamide, also were effective in attenuating alloxan-and streptozotocin-induced B-cell toxicity. Tests of the hydroxyl-scavenging ability of the three streptozotocin antagonists revealed that 3-aminobenzamide, nicotinamide and 1,1-dimethyl urea were effec-tive scavengers of this free radical. Conversely, 1,1-dimethyl urea, although not as potent as 3-aminobenzamide or nicotinamide, was found to inhibit poly (ADP-ribose) synthetase. These data indicate that these chemicals most likely attenuate alloxan-induced toxicity by scavenging the hydroxyl radical and diminish streptozotocin-induced toxicity by inactivation of the poly (ADP-ribose) system.

Acta physiologica Scandinavica. Supplementum

1. Acta Physiol Scand Suppl. 1986;548:101-7. Role of free radicals in ischemia-reperfusion injury... more 1. Acta Physiol Scand Suppl. 1986;548:101-7. Role of free radicals in ischemia-reperfusion injury to the liver. Adkison D, Höllwarth ME, Benoit JN, Parks DA, McCord JM, Granger DN. PMID: 3463123 [PubMed - indexed for MEDLINE]. Publication Types: ...

Research communications in chemical pathology and pharmacology

Single doses of ethanol (5 g/kg, intragastric) produce oxidative stress in the liver as well as i... more Single doses of ethanol (5 g/kg, intragastric) produce oxidative stress in the liver as well as in the heart. The metabolism of acetaldehyde through xanthine oxidase appears to play an important role in the production of oxidative stress in the heart, but it has only a contributory role in the liver. It is suggested that, as oxidative stress through lipid peroxidation may produce organ pathology, the metabolic pathway of acetaldehyde through xanthine oxidase may be one of the mechanisms which mediate cardiac pathology in alcoholism.

The American journal of physiology, 1984

Oxygen-derived free radicals have been proposed as general mediators of tissue injury in a variet... more Oxygen-derived free radicals have been proposed as general mediators of tissue injury in a variety of disease states. Recent interest has focused on the possibility that free radicals may be involved in ischemic myocardial damage. However, the exact types of damage that result from myocardial exposure to free radicals remains to be established. The purpose of this study was to evaluate the effects of superoxide and hydroxyl radicals on myocardial structure and function in an isolated perfused rabbit interventricular septal preparation. Superoxide was generated by adding purine (2.3 mM) and xanthine oxidase (0.01 U/ml) to the physiological solutions perfusing the septa. Hydroxyl radical generation was catalyzed by the addition of 2.4 microM Fe3+-loaded transferrin to the system. Exposure of normal septa to superoxide-generating solutions resulted in the development of structural alterations in the vascular endothelium including the development of vacuoles. Membranous cellular debris ...

Gastroenterology, 1981

One hour of regional ischemia significantly increases the permeability of intestinal capillaries.... more One hour of regional ischemia significantly increases the permeability of intestinal capillaries. The role of local humoral agents in the genesis of an increased capillary permeability in the ischemic bowel was assessed using specific antagonists to substances commonly believed to be involved in the pathogenesis of ischemic states. Capillary permeability estimates in autoperfused segments of cat ileum were derived from the relationship between lymph-to-plasma protein concentration ratio and lymph flow. Pretreatment of the ileal segments with either benadryl + cimetidine, indomethacin, or methylprednisolone did not significantly alter the permeability increase induced by regional ischemia. Pretreatment with superoxide dismutase (SOD), a superoxide radical scavenging enzyme, significantly attenuated the capillary permeability change induced by regional ischemia. Intravenous E. coli endotoxin administration in normotensive preparations increased intestinal capillary permeability; howev...

Journal of applied physiology (Bethesda, Md. : 1985), 1990

The effect of ischemia reperfusion or hypoxia reoxygenation on pulmonary vascular permeability an... more The effect of ischemia reperfusion or hypoxia reoxygenation on pulmonary vascular permeability and resistance was studied in 25 isolated blood-perfused dog lungs. Vascular permeability, assessed by determining filtration coefficient (Kf), and vascular resistances were measured at the beginning and end of the experiment. Ischemia reperfusion was produced by occluding blood flow to the lung for 3 h and reperfusing for 1 h, whereas hypoxia reoxygenation was obtained by ventilating the lung with 95% N2-5% CO2 for 3 h and then ventilating with 95% O2-5% CO2 for 1 h with no interruption of perfusion. There was a significant increase in Kf in both ischemia reperfusion and hypoxia reoxygenation groups (51 and 85%, respectively), and total vascular resistance increased greatly in both groups (386 and 532%, respectively). Two additional groups were also studied in which the ischemia reperfusion or hypoxia reoxygenation lungs were pretreated with allopurinol (20 micrograms/ml). The Kf did not ...

Advances in Myocardiology, 1985

ABSTRACT

Journal of Dietary Supplements, 2010

Therapeutic options for Duchenne muscular dystrophy (DMD), the most common and lethal neuromuscul... more 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 ® is an over-the-counter supplement with the ability to induce antioxidant enzymes. In this study we investigated whether Protandim ® 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 ® -supplemented standard rodent chow. The diets were continued for 6-week and 6-month studies. The endpoints included the oxidative stress marker thiobarbituric acid-reactive substances (TBARS), plasma osteopontin (OPN), plasma paraoxonase (PON1) activity, H&E histology, gadolinium-enhanced magnetic resonance imaging (MRI) of leg muscle and motor functional measurements. The Protandim ® chow diet in mdx mice for 6 months was safe and well tolerated. After 6 months of Protandim ® , a 48% average decrease in plasma TBARS was seen; 0.92 nmol/mg protein in controls versus 0.48 nmol/mg protein in the Protandim ® group (p = .006). At 6 months, plasma OPN was decreased by 57% (p = .001) in the Protandim ® -treated mice. Protandim ® increased the plasma antioxidant enzyme PON1 activity by 35% (p = .018). After 6 months, the mdx mice with Protandim ® showed 38% less MRI signal abnormality (p = .07) than mice on control diet. In this 6-month mdx mouse study, Protandim ® did not significantly alter motor function nor histological criteria.

ABSTRACT Consumption of a high salt (HS) diet results in vascular oxidant stress and impairs endo... more ABSTRACT Consumption of a high salt (HS) diet results in vascular oxidant stress and impairs endothelium-dependent relaxation in a variety of human and experimental models. Nuclear factor erythroid-2-related factor 2 (Nrf2) is a transcription factor that induces the expression of many critical antioxidant genes. We measured protein expression of Nrf2 and its cytosolic inhibitor, kelch-like ECH-associated protein 1 (Keap1), in mesenteric and cerebral arterial homogenates from Sprague-Dawley (SD) rats fed HS (4% NaCl), low salt (LS), or HS with low dose angiotensin II (ANG II) infusion to restore normal plasma ANG II levels. While Nrf2 expression was similar between groups, Keap1 expression was significantly lower in ANG II-infused rats (p < 0.05). The Nrf2:Keap1 ratio normalized to LS was significantly increased in both mesenteric (LS = 100.00% ± 19.76; HS = 176.34% ± 29.98; HS + ANG II = 561.44% ± 210.39) and cerebral (LS = 100.00% ± 16.21; HS = 181.67% ± 69.31; HS + ANG II = 677.55% ± 172.38) arterial beds. The dietary supplement Protandim, shown to induce Nrf2 expression, improved endothelium-dependent relaxation to acetylcholine in salt-fed SD rats (HS = 0.50 μm ± 0.96; HS + Protandim = 6.67 μm ± 1.28; p = 0.008) and hamsters (HS = 1.33 μm ± 0.52; HS + Protandim = 5.60 μm ± 0.68; p < 0.001 ). Together, these data suggest a functional role for the Nrf2 antioxidant defense system in preventing salt-induced vascular dysfunction.

PLoS ONE, 2010

Protandim, a well defined dietary combination of 5 well-established medicinal plants, is known to... more 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. Therefore, we investigated the effects of the Protandim diet on apoptosis; and proposed a novel mechanism of chemoprevention utilized by the Protandim dietary combination. Interestingly, Protandim suppressed DMBA/TPA induced cutaneous apoptosis. Recently, more attention has been focused on transcription-independent mechanisms of the tumor suppressor, p53, that mediate apoptosis. It is known that cytoplasmic p53 rapidly translocates to the mitochondria in response to pro-apoptotic stress. Our results showed that Protandim suppressed the mitochondrial translocation of p53 and mitochondrial outer membrane proteins such as Bax. We examined the levels of p53 and MnSOD expression/activity in murine skin JB6 promotion sensitive (P+) and promotionresistant (P-) epidermal cells. Interestingly, p53 was induced only in P+ cells, not P-cells; whereas MnSOD is highly expressed in P-cells when compared to P+ cells. In addition, wild-type p53 was transfected into JB6 P-cells. We found that the introduction of wild-type p53 promoted transformation in JB6 P-cells. Our results suggest that suppression of p53 and induction of MnSOD may play an important role in the tumor suppressive activity of Protandim.

PLoS ONE, 2009

Oxidative stress is an important contributor to cancer development. Consistent with that, antioxi... more 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. To investigate whether Protandim can suppress tumor formation by a dietary approach, a two-stage mouse skin carcinogenesis study was performed. At the end of the study, the mice on a Protandimcontaining basal diet had similar body weight compared with those on the basal diet, which indicated no overt toxicity by Protandim. After three weeks on the diets, there was a significant increase in the expression levels of SOD and catalase, in addition to the increases in SOD activities. Importantly, at the end of the carcinogenesis study, both skin tumor incidence and multiplicity were reduced in the mice on the Protandim diet by 33% and 57% respectively, compared with those on basal diet. Biochemical and histological studies revealed that the Protandim diet suppressed tumor promoter-induced oxidative stress (evidenced by reduction of protein carbonyl levels), cell proliferation (evidenced by reduction of skin hyperplasia and suppression of PKC/JNK/Jun pathway), and inflammation (evidenced by reduction of ICAM-1/VCAM-1 expression, NF-kB binding activity, and nuclear p65/p50 levels). Overall, induction of antioxidant enzymes by Protandim may serve as a practical and potent approach for cancer prevention.

Free Radical Biology and Medicine, 2013

Diabetologia, 1984

In studies to evaluate possible inhibitors of the Bcell toxin, streptozotocin, the superoxide sca... more In studies to evaluate possible inhibitors of the Bcell toxin, streptozotocin, the superoxide scavenger, superoxide dismutase, did not prevent or reduce the toxic effects of streptozotocin as determined by loss of insulin secretion from rat pancreatic B cells in monolayer culture. However, 1,l-dimethyl urea, a scavenger of the hydroxyl radical, did afford significant protection. Both scavengers diminished the cytotoxic effects of alloxan. The inhibitors of poly (ADP-ribose) synthetase, 3-aminobenzamide and nicotinamide, also were effective in attenuating alloxan-and streptozotocin-induced B-cell toxicity. Tests of the hydroxyl-scavenging ability of the three streptozotocin antagonists revealed that 3-aminobenzamide, nicotinamide and 1,1-dimethyl urea were effec-tive scavengers of this free radical. Conversely, 1,1-dimethyl urea, although not as potent as 3-aminobenzamide or nicotinamide, was found to inhibit poly (ADP-ribose) synthetase. These data indicate that these chemicals most likely attenuate alloxan-induced toxicity by scavenging the hydroxyl radical and diminish streptozotocin-induced toxicity by inactivation of the poly (ADP-ribose) system.

Canadian Journal of Physiology and Pharmacology, 1982

The superoxide radical plays major roles in the neutrophil-medicated acute inflammatory response ... more The superoxide radical plays major roles in the neutrophil-medicated acute inflammatory response and in postischemic tissue injury, although the sources and actions of the radical are quite different in these two pathological states. While neutrophils produce superoxide for the primary purpose of aiding in the killing of ingested microbes, a second useful function has evolved. The superoxide released from actively phagocytosing neutrophils serves to attract more neutrophils by reacting with, and activating, a latent chemotactic factor present in plasma. Superoxide dismutase, by preventing the activation of this superoxide-dependent chemotactic factor, exerts potent anti-inflammatory action. During ischemia, energy-starved tissues catabolize ATP to hypoxanthine. Calcium transients in these cells appear to activate a calmodulin regulated protease which attacks the enzyme xanthine dehydrogenase, converting it to a xanthine oxidase capable of superoxide generation. When the tissue is reperfused and reoxygenated, all the necessary components are present (xanthine oxidase, hypoxanthine, and oxygen) to produce a burst of superoxide which results in extensive tissue damage. Ischemic tissues are protected by superoxide dismutase or allupurinol, an inhibitor of xanthine oxidase.

AJP: Lung Cellular and Molecular Physiology, 2012

ABSTRACT Alcohol use disorders (AUDs), including alcohol abuse and dependence, have been linked t... more ABSTRACT Alcohol use disorders (AUDs), including alcohol abuse and dependence, have been linked to the development of acute lung injury (ALI). Prior clinical investigations suggested an association between AUDs and abnormal alveolar epithelial permeability mediated through pulmonary oxidative stress that may partially explain this relationship. We sought to determine if correcting pulmonary oxidative stress in the setting of AUDs would normalize alveolar epithelial permeability in a double-blinded, randomized, placebo-controlled trial of Protandim, a nutraceutical reported to enhance antioxidant activity. We randomized 30 otherwise healthy AUD subjects to receive directly observed inpatient oral therapy with either Protandim (1,350 mg/day) or placebo. Subjects underwent bronchoalveolar lavage (BAL) and blood sampling before study drug administration and after 7 days of therapy; all AUD subjects completed the study protocol without adverse events. BAL total protein was measured at each timepoint as an indicator of alveolar epithelial permeability. In subjects with AUDs, before study drug initiation, BAL total protein values were not significantly higher than in 11 concurrently enrolled controls (P = 0.07). Over the 7-day study period, AUD subjects did not exhibit a significant change in BAL total protein, regardless of their randomization to Protandim {n = 14, -2% [intraquartile range (IQR), -56-146%]} or to placebo [n = 16, 77% (IQR -20-290%); P = 0.19]. Additionally, among those with AUDs, no significant changes in BAL oxidative stress indexes, epithelial growth factor, fibroblast growth factor, interleukin-1β, or interleukin-10 were observed regardless of drug type received. Plasma thiobarbituric acid reactive substances, a marker of lipid peroxidation, decreased significantly over time among AUD subjects randomized to placebo (P < 0.01). These results suggest that Protandim for 7 days in individuals with AUDs who are newly abstinent does not alter alveolar epithelial permeability. However, our work demonstrates the feasibility of safely conducting clinical trials that include serial bronchoscopies in a vulnerable population at risk for acute lung injury.

The American Journal of Physiology, Jul 1, 1984

Oxygen-derived free radicals have been proposed as general mediators of tissue injury in a variet... more Oxygen-derived free radicals have been proposed as general mediators of tissue injury in a variety of disease states. Recent interest has focused on the possibility that free radicals may be involved in ischemic myocardial damage. However, the exact types of damage that result from myocardial exposure to free radicals remains to be established. The purpose of this study was to evaluate the effects of superoxide and hydroxyl radicals on myocardial structure and function in an isolated perfused rabbit interventricular septal preparation. Superoxide was generated by adding purine (2.3 mM) and xanthine oxidase (0.01 U/ml) to the physiological solutions perfusing the septa. Hydroxyl radical generation was catalyzed by the addition of 2.4 microM Fe3+-loaded transferrin to the system. Exposure of normal septa to superoxide-generating solutions resulted in the development of structural alterations in the vascular endothelium including the development of vacuoles. Membranous cellular debris was evident in the extracellular space and within the vessels. Cardiac myocytes showed evidence of mild alterations. Exposure of septa to solutions capable of generating hydroxyl radicals resulted in more extensive and severe damage. Vascular endothelial cells showed evidence of vacuoles or blebs and edema. Severe swelling of mitochondria was evident in cardiac myocytes and vascular endothelial cells. In addition, myocytes often showed blebbing of the basement membrane. Normal septa exposed to superoxide showed no significant decrease in developed tension, whereas hydroxyl radical exposure resulted in a significant decrease in myocardial function.(ABSTRACT TRUNCATED AT 250 WORDS)

The Faseb Journal, Apr 1, 2013

ABSTRACT Consumption of a high salt (HS) diet results in vascular oxidant stress and impairs endo... more ABSTRACT Consumption of a high salt (HS) diet results in vascular oxidant stress and impairs endothelium-dependent relaxation in a variety of human and experimental models. Nuclear factor erythroid-2-related factor 2 (Nrf2) is a transcription factor that induces the expression of many critical antioxidant genes. We measured protein expression of Nrf2 and its cytosolic inhibitor, kelch-like ECH-associated protein 1 (Keap1), in mesenteric and cerebral arterial homogenates from Sprague-Dawley (SD) rats fed HS (4% NaCl), low salt (LS), or HS with low dose angiotensin II (ANG II) infusion to restore normal plasma ANG II levels. While Nrf2 expression was similar between groups, Keap1 expression was significantly lower in ANG II-infused rats (p < 0.05). The Nrf2:Keap1 ratio normalized to LS was significantly increased in both mesenteric (LS = 100.00% ± 19.76; HS = 176.34% ± 29.98; HS + ANG II = 561.44% ± 210.39) and cerebral (LS = 100.00% ± 16.21; HS = 181.67% ± 69.31; HS + ANG II = 677.55% ± 172.38) arterial beds. The dietary supplement Protandim, shown to induce Nrf2 expression, improved endothelium-dependent relaxation to acetylcholine in salt-fed SD rats (HS = 0.50 μm ± 0.96; HS + Protandim = 6.67 μm ± 1.28; p = 0.008) and hamsters (HS = 1.33 μm ± 0.52; HS + Protandim = 5.60 μm ± 0.68; p < 0.001 ). Together, these data suggest a functional role for the Nrf2 antioxidant defense system in preventing salt-induced vascular dysfunction.

Diabetologia, 1984

In studies to evaluate possible inhibitors of the Bcell toxin, streptozotocin, the superoxide sca... more In studies to evaluate possible inhibitors of the Bcell toxin, streptozotocin, the superoxide scavenger, superoxide dismutase, did not prevent or reduce the toxic effects of streptozotocin as determined by loss of insulin secretion from rat pancreatic B cells in monolayer culture. However, 1,l-dimethyl urea, a scavenger of the hydroxyl radical, did afford significant protection. Both scavengers diminished the cytotoxic effects of alloxan. The inhibitors of poly (ADP-ribose) synthetase, 3-aminobenzamide and nicotinamide, also were effective in attenuating alloxan-and streptozotocin-induced B-cell toxicity. Tests of the hydroxyl-scavenging ability of the three streptozotocin antagonists revealed that 3-aminobenzamide, nicotinamide and 1,1-dimethyl urea were effec-tive scavengers of this free radical. Conversely, 1,1-dimethyl urea, although not as potent as 3-aminobenzamide or nicotinamide, was found to inhibit poly (ADP-ribose) synthetase. These data indicate that these chemicals most likely attenuate alloxan-induced toxicity by scavenging the hydroxyl radical and diminish streptozotocin-induced toxicity by inactivation of the poly (ADP-ribose) system.

Acta physiologica Scandinavica. Supplementum

1. Acta Physiol Scand Suppl. 1986;548:101-7. Role of free radicals in ischemia-reperfusion injury... more 1. Acta Physiol Scand Suppl. 1986;548:101-7. Role of free radicals in ischemia-reperfusion injury to the liver. Adkison D, Höllwarth ME, Benoit JN, Parks DA, McCord JM, Granger DN. PMID: 3463123 [PubMed - indexed for MEDLINE]. Publication Types: ...

Research communications in chemical pathology and pharmacology

Single doses of ethanol (5 g/kg, intragastric) produce oxidative stress in the liver as well as i... more Single doses of ethanol (5 g/kg, intragastric) produce oxidative stress in the liver as well as in the heart. The metabolism of acetaldehyde through xanthine oxidase appears to play an important role in the production of oxidative stress in the heart, but it has only a contributory role in the liver. It is suggested that, as oxidative stress through lipid peroxidation may produce organ pathology, the metabolic pathway of acetaldehyde through xanthine oxidase may be one of the mechanisms which mediate cardiac pathology in alcoholism.

The American journal of physiology, 1984

Oxygen-derived free radicals have been proposed as general mediators of tissue injury in a variet... more Oxygen-derived free radicals have been proposed as general mediators of tissue injury in a variety of disease states. Recent interest has focused on the possibility that free radicals may be involved in ischemic myocardial damage. However, the exact types of damage that result from myocardial exposure to free radicals remains to be established. The purpose of this study was to evaluate the effects of superoxide and hydroxyl radicals on myocardial structure and function in an isolated perfused rabbit interventricular septal preparation. Superoxide was generated by adding purine (2.3 mM) and xanthine oxidase (0.01 U/ml) to the physiological solutions perfusing the septa. Hydroxyl radical generation was catalyzed by the addition of 2.4 microM Fe3+-loaded transferrin to the system. Exposure of normal septa to superoxide-generating solutions resulted in the development of structural alterations in the vascular endothelium including the development of vacuoles. Membranous cellular debris ...

Gastroenterology, 1981

One hour of regional ischemia significantly increases the permeability of intestinal capillaries.... more One hour of regional ischemia significantly increases the permeability of intestinal capillaries. The role of local humoral agents in the genesis of an increased capillary permeability in the ischemic bowel was assessed using specific antagonists to substances commonly believed to be involved in the pathogenesis of ischemic states. Capillary permeability estimates in autoperfused segments of cat ileum were derived from the relationship between lymph-to-plasma protein concentration ratio and lymph flow. Pretreatment of the ileal segments with either benadryl + cimetidine, indomethacin, or methylprednisolone did not significantly alter the permeability increase induced by regional ischemia. Pretreatment with superoxide dismutase (SOD), a superoxide radical scavenging enzyme, significantly attenuated the capillary permeability change induced by regional ischemia. Intravenous E. coli endotoxin administration in normotensive preparations increased intestinal capillary permeability; howev...

Journal of applied physiology (Bethesda, Md. : 1985), 1990

The effect of ischemia reperfusion or hypoxia reoxygenation on pulmonary vascular permeability an... more The effect of ischemia reperfusion or hypoxia reoxygenation on pulmonary vascular permeability and resistance was studied in 25 isolated blood-perfused dog lungs. Vascular permeability, assessed by determining filtration coefficient (Kf), and vascular resistances were measured at the beginning and end of the experiment. Ischemia reperfusion was produced by occluding blood flow to the lung for 3 h and reperfusing for 1 h, whereas hypoxia reoxygenation was obtained by ventilating the lung with 95% N2-5% CO2 for 3 h and then ventilating with 95% O2-5% CO2 for 1 h with no interruption of perfusion. There was a significant increase in Kf in both ischemia reperfusion and hypoxia reoxygenation groups (51 and 85%, respectively), and total vascular resistance increased greatly in both groups (386 and 532%, respectively). Two additional groups were also studied in which the ischemia reperfusion or hypoxia reoxygenation lungs were pretreated with allopurinol (20 micrograms/ml). The Kf did not ...

Advances in Myocardiology, 1985

ABSTRACT

Journal of Dietary Supplements, 2010

Therapeutic options for Duchenne muscular dystrophy (DMD), the most common and lethal neuromuscul... more 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 ® is an over-the-counter supplement with the ability to induce antioxidant enzymes. In this study we investigated whether Protandim ® 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 ® -supplemented standard rodent chow. The diets were continued for 6-week and 6-month studies. The endpoints included the oxidative stress marker thiobarbituric acid-reactive substances (TBARS), plasma osteopontin (OPN), plasma paraoxonase (PON1) activity, H&E histology, gadolinium-enhanced magnetic resonance imaging (MRI) of leg muscle and motor functional measurements. The Protandim ® chow diet in mdx mice for 6 months was safe and well tolerated. After 6 months of Protandim ® , a 48% average decrease in plasma TBARS was seen; 0.92 nmol/mg protein in controls versus 0.48 nmol/mg protein in the Protandim ® group (p = .006). At 6 months, plasma OPN was decreased by 57% (p = .001) in the Protandim ® -treated mice. Protandim ® increased the plasma antioxidant enzyme PON1 activity by 35% (p = .018). After 6 months, the mdx mice with Protandim ® showed 38% less MRI signal abnormality (p = .07) than mice on control diet. In this 6-month mdx mouse study, Protandim ® did not significantly alter motor function nor histological criteria.

ABSTRACT Consumption of a high salt (HS) diet results in vascular oxidant stress and impairs endo... more ABSTRACT Consumption of a high salt (HS) diet results in vascular oxidant stress and impairs endothelium-dependent relaxation in a variety of human and experimental models. Nuclear factor erythroid-2-related factor 2 (Nrf2) is a transcription factor that induces the expression of many critical antioxidant genes. We measured protein expression of Nrf2 and its cytosolic inhibitor, kelch-like ECH-associated protein 1 (Keap1), in mesenteric and cerebral arterial homogenates from Sprague-Dawley (SD) rats fed HS (4% NaCl), low salt (LS), or HS with low dose angiotensin II (ANG II) infusion to restore normal plasma ANG II levels. While Nrf2 expression was similar between groups, Keap1 expression was significantly lower in ANG II-infused rats (p < 0.05). The Nrf2:Keap1 ratio normalized to LS was significantly increased in both mesenteric (LS = 100.00% ± 19.76; HS = 176.34% ± 29.98; HS + ANG II = 561.44% ± 210.39) and cerebral (LS = 100.00% ± 16.21; HS = 181.67% ± 69.31; HS + ANG II = 677.55% ± 172.38) arterial beds. The dietary supplement Protandim, shown to induce Nrf2 expression, improved endothelium-dependent relaxation to acetylcholine in salt-fed SD rats (HS = 0.50 μm ± 0.96; HS + Protandim = 6.67 μm ± 1.28; p = 0.008) and hamsters (HS = 1.33 μm ± 0.52; HS + Protandim = 5.60 μm ± 0.68; p < 0.001 ). Together, these data suggest a functional role for the Nrf2 antioxidant defense system in preventing salt-induced vascular dysfunction.

PLoS ONE, 2010

Protandim, a well defined dietary combination of 5 well-established medicinal plants, is known to... more 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. Therefore, we investigated the effects of the Protandim diet on apoptosis; and proposed a novel mechanism of chemoprevention utilized by the Protandim dietary combination. Interestingly, Protandim suppressed DMBA/TPA induced cutaneous apoptosis. Recently, more attention has been focused on transcription-independent mechanisms of the tumor suppressor, p53, that mediate apoptosis. It is known that cytoplasmic p53 rapidly translocates to the mitochondria in response to pro-apoptotic stress. Our results showed that Protandim suppressed the mitochondrial translocation of p53 and mitochondrial outer membrane proteins such as Bax. We examined the levels of p53 and MnSOD expression/activity in murine skin JB6 promotion sensitive (P+) and promotionresistant (P-) epidermal cells. Interestingly, p53 was induced only in P+ cells, not P-cells; whereas MnSOD is highly expressed in P-cells when compared to P+ cells. In addition, wild-type p53 was transfected into JB6 P-cells. We found that the introduction of wild-type p53 promoted transformation in JB6 P-cells. Our results suggest that suppression of p53 and induction of MnSOD may play an important role in the tumor suppressive activity of Protandim.

PLoS ONE, 2009

Oxidative stress is an important contributor to cancer development. Consistent with that, antioxi... more 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. To investigate whether Protandim can suppress tumor formation by a dietary approach, a two-stage mouse skin carcinogenesis study was performed. At the end of the study, the mice on a Protandimcontaining basal diet had similar body weight compared with those on the basal diet, which indicated no overt toxicity by Protandim. After three weeks on the diets, there was a significant increase in the expression levels of SOD and catalase, in addition to the increases in SOD activities. Importantly, at the end of the carcinogenesis study, both skin tumor incidence and multiplicity were reduced in the mice on the Protandim diet by 33% and 57% respectively, compared with those on basal diet. Biochemical and histological studies revealed that the Protandim diet suppressed tumor promoter-induced oxidative stress (evidenced by reduction of protein carbonyl levels), cell proliferation (evidenced by reduction of skin hyperplasia and suppression of PKC/JNK/Jun pathway), and inflammation (evidenced by reduction of ICAM-1/VCAM-1 expression, NF-kB binding activity, and nuclear p65/p50 levels). Overall, induction of antioxidant enzymes by Protandim may serve as a practical and potent approach for cancer prevention.

Free Radical Biology and Medicine, 2013

Diabetologia, 1984

In studies to evaluate possible inhibitors of the Bcell toxin, streptozotocin, the superoxide sca... more In studies to evaluate possible inhibitors of the Bcell toxin, streptozotocin, the superoxide scavenger, superoxide dismutase, did not prevent or reduce the toxic effects of streptozotocin as determined by loss of insulin secretion from rat pancreatic B cells in monolayer culture. However, 1,l-dimethyl urea, a scavenger of the hydroxyl radical, did afford significant protection. Both scavengers diminished the cytotoxic effects of alloxan. The inhibitors of poly (ADP-ribose) synthetase, 3-aminobenzamide and nicotinamide, also were effective in attenuating alloxan-and streptozotocin-induced B-cell toxicity. Tests of the hydroxyl-scavenging ability of the three streptozotocin antagonists revealed that 3-aminobenzamide, nicotinamide and 1,1-dimethyl urea were effec-tive scavengers of this free radical. Conversely, 1,1-dimethyl urea, although not as potent as 3-aminobenzamide or nicotinamide, was found to inhibit poly (ADP-ribose) synthetase. These data indicate that these chemicals most likely attenuate alloxan-induced toxicity by scavenging the hydroxyl radical and diminish streptozotocin-induced toxicity by inactivation of the poly (ADP-ribose) system.

Canadian Journal of Physiology and Pharmacology, 1982

The superoxide radical plays major roles in the neutrophil-medicated acute inflammatory response ... more The superoxide radical plays major roles in the neutrophil-medicated acute inflammatory response and in postischemic tissue injury, although the sources and actions of the radical are quite different in these two pathological states. While neutrophils produce superoxide for the primary purpose of aiding in the killing of ingested microbes, a second useful function has evolved. The superoxide released from actively phagocytosing neutrophils serves to attract more neutrophils by reacting with, and activating, a latent chemotactic factor present in plasma. Superoxide dismutase, by preventing the activation of this superoxide-dependent chemotactic factor, exerts potent anti-inflammatory action. During ischemia, energy-starved tissues catabolize ATP to hypoxanthine. Calcium transients in these cells appear to activate a calmodulin regulated protease which attacks the enzyme xanthine dehydrogenase, converting it to a xanthine oxidase capable of superoxide generation. When the tissue is reperfused and reoxygenated, all the necessary components are present (xanthine oxidase, hypoxanthine, and oxygen) to produce a burst of superoxide which results in extensive tissue damage. Ischemic tissues are protected by superoxide dismutase or allupurinol, an inhibitor of xanthine oxidase.

AJP: Lung Cellular and Molecular Physiology, 2012

ABSTRACT Alcohol use disorders (AUDs), including alcohol abuse and dependence, have been linked t... more ABSTRACT Alcohol use disorders (AUDs), including alcohol abuse and dependence, have been linked to the development of acute lung injury (ALI). Prior clinical investigations suggested an association between AUDs and abnormal alveolar epithelial permeability mediated through pulmonary oxidative stress that may partially explain this relationship. We sought to determine if correcting pulmonary oxidative stress in the setting of AUDs would normalize alveolar epithelial permeability in a double-blinded, randomized, placebo-controlled trial of Protandim, a nutraceutical reported to enhance antioxidant activity. We randomized 30 otherwise healthy AUD subjects to receive directly observed inpatient oral therapy with either Protandim (1,350 mg/day) or placebo. Subjects underwent bronchoalveolar lavage (BAL) and blood sampling before study drug administration and after 7 days of therapy; all AUD subjects completed the study protocol without adverse events. BAL total protein was measured at each timepoint as an indicator of alveolar epithelial permeability. In subjects with AUDs, before study drug initiation, BAL total protein values were not significantly higher than in 11 concurrently enrolled controls (P = 0.07). Over the 7-day study period, AUD subjects did not exhibit a significant change in BAL total protein, regardless of their randomization to Protandim {n = 14, -2% [intraquartile range (IQR), -56-146%]} or to placebo [n = 16, 77% (IQR -20-290%); P = 0.19]. Additionally, among those with AUDs, no significant changes in BAL oxidative stress indexes, epithelial growth factor, fibroblast growth factor, interleukin-1β, or interleukin-10 were observed regardless of drug type received. Plasma thiobarbituric acid reactive substances, a marker of lipid peroxidation, decreased significantly over time among AUD subjects randomized to placebo (P < 0.01). These results suggest that Protandim for 7 days in individuals with AUDs who are newly abstinent does not alter alveolar epithelial permeability. However, our work demonstrates the feasibility of safely conducting clinical trials that include serial bronchoscopies in a vulnerable population at risk for acute lung injury.