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SOD-superoxide dismutase- powerful anti inflammatory

Rheumatol Int. 1994;14(2):77-81. : Anti-inflammatory effects of recombinant human manganese superoxide dismutase on adjuvant arthritis in rats.
Shingu M, Takahashi S, Ito M, Hamamatu N, Suenaga Y, Ichibangase Y, Nobunaga M.
Department of Clinical Immunology, Kyushu University, Beppu, Japan.

The anti-inflammatory effects of recombinant human manganese superoxide dismutase on adjuvant arthritis was investigated. Local application of this manganese superoxide dismutase given every 2 days not only significantly reduced foot swelling but also retarded radiological bone destruction in adjuvant arthritis. Copper zinc superoxide dismutase had little effect on foot swelling.
Biochim Biophys Acta. 2002 Aug 19;1564(1):227-36. : Superoxide dismutase entrapped in long-circulating liposomes: formulation design and therapeutic activity in rat adjuvant arthritis.
Luisa Corvo M, Jorge JC, van't Hof R, Cruz ME, Crommelin DJ, Storm G. Department of Biotechnology, Instituto Nacional de Engenharia e Tecnologia Industrial (INETI), Unidade de Novas Formas de Agentes Bioactivos, Estrada do Paco do Lumiar 22, 1649-038 Lisbon, Portugal.
luisa.corvo@ineti.pt

The aim of this study was to investigate whether long-circulating liposomes can improve the anti-inflammatory activity of superoxide dismutase (SOD). Small-sized poly(ethyleneglycol) (PEG)-liposomes containing SOD were prepared via different preparation protocols and characterized in terms of encapsulation efficiency (EE), size, enzymatic activity and protein structure, to establish conditions where high EE can be combined with preservation of enzyme activity and structure. It was observed that structural information from circular dichroism analyses does not correlate with data on enzyme activity. SOD-containing PEG-liposomes prepared by the dehydration-rehydration method appeared to represent the most attractive formulation for in vivo evaluation. The therapeutic potential of selected SOD-containing PEG-liposomes was established and compared with SOD entrapped in stearylamine (SA)-liposomes and 'free' SOD upon intravenous (i.v.) injection in an arthritic rat model. Both small PEG-liposomes and SA-liposomes showed a superior therapeutic activity compared to 'free' SOD, with PEG-liposomes inducing stronger anti-inflammatory effects than SA-liposomes.


1: Acta Pharmacol Sin. 2002 May;23(5):439-44. : Anti-inflammatory effect of recombinant human superoxide dismutase in rats and mice and its mechanism.
Zhang Y, Wang JZ, Wu YJ, Li WG.
National Institute for the Control of Pharmaceutical and Biological Products, Beijing 100050, China. bjzhangyi@163.net.

AIM: To investigate the anti-inflammatory effects and mechanism of recombinant human superoxide dismutase (rhSOD). METHODS: Inflammation models such as croton oil-induced ear swelling and carrageenan-induced hind paw edema in mice and rats were prepared. The nitric oxide synthase (NOS ) activity was measured by NADPH-diaphoras stain assay, N-acetyl-beta-D-glucosaminidase (beta-NAG) activity by spectrophotography, malondialdehyde (MDA) content by thiobarbituric acid (TBA) fluorescence technique, and interleukin-1beta (IL -1beta), tumor necrosis factor alpha (TNF alpha), and IL-8 content by radioimmunoassay (RIA). RESULTS: rhSOD 20-80 mg/kg ip, 40-80 mg/kg im, and 80 mg/kg ip significantly inhibited carrageenan-induced paw edema in rats, croton oil-induced ear swelling in mice, and carrageenan-induced hind paw edema in mice, respectively. In the rat arthritis induced by carrageenan, rhSOD 40 mg/kg reduced MDA content in inflamed paws, inhibited NOS activity, and lowered the content of IL-1beta and TNFalpha in exudate significantly. The inhibitory effect of rhSOD 40 mg/kg ip on IL-1beta production was more evident than that of dexamethasone 2 mg/kg ip. Also rhSOD obviously inhibited neutrophil infiltration; However, rhSOD had no effect on beta-NAG activity in exudate. CONCLUSION: rhSOD has anti-inflammatory effect on experimental inflammation in rats and mice, and its mechanisms are relevant to oxygen free radical scavenging, anti-lipid peroxidation, inhibition of neutrophil infiltration, and formation of inflammatory cytokines.
1: Arthritis Rheum. 2001 Dec;44(12):2909-21. : Amelioration of joint disease in a rat model of collagen-induced arthritis by M40403, a superoxide dismutase mimetic.
Salvemini D, Mazzon E, Dugo L, Serraino I, De Sarro A, Caputi AP, Cuzzocrea S.
MetaPhore Pharmaceuticals, St. Louis, Missouri 63114, USA. dsalvemini@metaphore.com

OBJECTIVE: To investigate the effects of M40403, a synthetic mimetic of superoxide dismutase (SOD), on collagen-induced arthritis (CIA) in rats. METHODS: CIA was elicited in Lewis rats by intradermal injection of 100 microl of an emulsion of bovine type II collagen (CII) in Freund's incomplete adjuvant at the base of the tail. A second injection was given on day 21. RESULTS: Immunization induced an erosive arthritis of the hind paws. Macroscopic evidence of CIA first appeared as periarticular erythema and edema in the hind paws by days 24-26 after the first injection, with a 100% incidence by days 27. Severity progressed over a 35-day period. Radiography revealed soft tissue swelling and focal resorption of bone, together with osteophyte formation in the tibiotarsal joint. Histopathologic features included erosion of the articular cartilage at the joint margins and subchondral bone resorption associated with bone-derived multinucleated cell-containing granulomatous lesions. Treatment with M40403 (2-10 mg/kg/day) starting at the onset of arthritis (day 25) ameliorated the clinical signs on days 26-35 and improved the histologic findings in the joint and paw. Immunohistochemical analysis for nitrotyrosine (a marker of peroxynitrite formation) and poly(ADP-ribose) polymerase (PARP; a nuclear enzyme activated by DNA single-strand damage) revealed positive staining in the inflamed joints of CII-treated rats, suggestive of the formation of peroxynitrite and DNA damage, both of which were markedly reduced by M40403 treatment. Radiographic evidence of protection from bone resorption, osteophyte formation, and soft tissue swelling was apparent in the tibiotarsal joints of M40403-treated rats. Arthritic rats treated with M40403 gained weight at the same rate and to the same extent as normal, nonarthritic rats. CONCLUSION: This study shows that a low molecular weight mimetic of SOD, M40403, attenuates the degree of chronic inflammation, tissue damage, and bone damage associated with CIA in the rat, and supports the possible use of SOD mimetics as therapeutic agents for the management of chronic diseases such as rheumatoid arthritis
Pharmazie. 2000 Jul;55(7):533-7. : Treatment of adjuvant arthritis in mice with yeast superoxide dismutase.
Ratcheva I, Stefanova Z, Vesselinova A, Nikolova S, Kujumdjieva A, Neychev H.
Institute of Microbiology, Bulgarian Academy of Sciences, Sofia, Bulgaria.
Yeast Cu/Zn superoxide dismutase (SODy) was used for treatment of adjuvant-induced arthritis in mice. SODy was applied intraperitoneally (i.p.) in doses of 10 mg/kg (30,000 U/kg) and 30 mg/kg (90,000 U/kg) one or three times daily on consecutive days. It was very effective in reducing the paw swelling whether administered before or immediately after induction or when the treatment began at the onset of inflammation or at the peak of the arthritic process. The effect of yeast SOD was compared to that of commercial SOD from bovine erythrocytes (SODb), as well as with indomethacin treatment. Histological data confirmed the antiinflammatory effect of yeast SOD. The schedules and doses tested did not elicit anti-SOD antibodies in serum.
Biochem Biophys Res Commun. 2000 Apr 21;270(3):714-6. : Improvement in circulating superoxide dismutase levels: role of nonsteroidal anti-inflammatory drugs in rheumatoid arthritis.
Nivsarkar M.
B. V. Patel Pharmaceutical Education and Research Development Centre, Thaltej-Gandhinagar Highway, Gujarat, Thaltej, Ahmedabad-380, 054, India.

Superoxide anion radical plays a significant role in inflammation, like rheumatoid arthritis. Superoxide dismutase enzyme known to dismutate superoxide anion radical does not play any significant role in this multisystem disease. This paper reports that very low levels of circulating superoxide dismutase levels are observed in patients with rheumatoid arthritis and these levels significantly improve with NSAID therapy. The possible mechanism of the action is discussed. Copyright 2000 Academic Press
Glycoconj J. 1997 Sep;14(6):723-8. : Anti-inflammatory activity of superoxide dismutase conjugated with sodium hyaluronate.
Sakurai K, Miyazaki K, Kodera Y, Nishimura H, Shingu M, Inada Y.
Toin Human Science and Technology Centre, Department of Materials Science and Technology, Toin University of Yokohama, Japan.

Superoxide dismutase (SOD) from bovine erythrocytes was conjugated with sodium hyaluronate (HA) with a mean molecular weight of 10(6) to have greater anti-inflammatory activity in vivo. Amino groups of SOD were coupled with carboxyl groups in the hyaluronate molecule using 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide. The HA-SOD conjugate was composed of 1.5 mol of SOD molecule per 1 mol of hyaluronate on the average, and retained 70% of the activity of unmodified SOD. The conjugate was essentially non-immunogenic in mice, and exhibited much higher anti-inflammatory activities than HA or SOD in models of inflammatory diseases such as ischemic oedema of the foot-pad in mice, carrageenin-induced pleurisy and adjuvant arthritis in rats
Hua Xi Yi Ke Da Xue Xue Bao. 1997 Mar;28(1):58-61. : [The anti-inflammatory effects of superoxide dismutase]
[Article in Chinese]
Xiong Y, Ye S, Liang Y, Song P, Zhou S.
Department of Pharmacology, School of Basic Medical Sciences, Chengdu.

This paper reports the anti-inflammatory effects of superoxide dismutase (SOD) from pig blood on inflammatory animal models. The experimental results have shown that SOD has significant anti-inflammatory effects. It inhibited carrageenin-induced foot-edema and croton oil induced granulation tissue edema of rats. It also inhibited arthritis induced by egg serum and Freund's adjuvant in rats. The effects were significantly dose-dependent.
atherogenesis
Formation of atheroma, important in the pathogenesis of arteriosclerosis.

1: Int J Biochem Cell Biol. 2004 Mar;36(3):460-71. : The pivotal role of scavenger receptor CD36 and phagocyte-derived oxidants in oxidized low density lipoprotein-induced adhesion to endothelial cells.
Kopprasch S, Pietzsch J, Westendorf T, Kruse HJ, Grassler J.
Department of Internal Medicine 3, Carl Gustav Carus Medical School, University of Technology Dresden, Fetscherstr. 74, D-01307, Dresden, Germany

Adhesion of phagocytes to endothelial cells constitutes a crucial step in atherogenesis. Oxidized low density lipoproteins (LDL) are supposed to facilitate the adhesion process. We investigated the molecular mechanisms by which mildly and extensively hypochlorite-oxidized LDL force adhesion of murine macrophages and human neutrophils to human umbilical venous endothelial cells. After 1h of co-incubation of macrophages, endothelial cells, and lipoproteins adhesion significantly increased to 160+/-13% (S.E.M., n=5) in the presence of mildly oxidized lipoprotein, and 210+/-11% (S.E.M., n=5) in the presence of extensively oxidized lipoprotein. Similar results were obtained with neutrophils. CD36 antibody (FA6-152) significantly reduced adhesion to 102+/-7% (S.E.M., n=5) using mildly oxidized low density lipoprotein and to 179+/-16% (S.E.M., n=5) using extensively oxidized low density lipoprotein. Native high density lipoprotein and to a lesser extent methionine-oxidized high density lipoprotein significantly counteracted the effects of low density lipoprotein. Prior incubation of endothelial cells with modified lipoproteins followed by their removal and subsequent incubation with macrophages or neutrophils resulted in only minor changes of adhesion. This suggests that the direct contact of low density lipoprotein with phagocytes followed by activation of a respiratory burst with release of reactive oxygen species facilitates the adhesion process. Accordingly, the addition of antioxidants (superoxide dismutase and catalase) to the co-incubation medium was followed by a significant decrease in phagocyte adhesion. It is concluded that oxidized low density lipoprotein-induced respiratory burst activation of phagocytes with subsequent release of oxidants constitutes a crucial step in promoting the adhesion of phagocytes to endothelial cells.

J Control Release. 2004 Feb 10;94(2-3):259-72. : Liposomes and disaccharides as carriers in spray-dried powder formulations of superoxide dismutase.
Lo Y, Tsai J, Kuo J.
Department of Pharmacy, Chia-Nan University of Pharmacy and Science, Hsien 717, Tainan, Taiwan, ROC

In this study, we aim to investigate the effects of disaccharides and liposome carriers on the activity, solid state characteristics, structural preservation, and aerosol powder performance of spray-dried superoxide dismutase (SOD) formulations. Sucrose, trehalose, and lactose were selected as stabilizing adjuvants in the spray-drying process. Dipalmitoyl phosphatidylcholine (DPPC) was the major lipid component for preparing liposomes. These SOD formulations were characterized with SOD activity assay, particle size, residual moisture content, scanning electron microscopy (SEM), electron spectroscopy for chemical analysis (ESCA), differential scanning calorimeter (DSC), and Fourier transform infrared (FT-IR) spectroscopy. We found that the inlet/outlet temperature of spray drying can be performed up to 168/122 degrees C with maintaining the activity of SOD in the SOD\DPPC\sucrose formulation for 98%. The SEM image of this formulation showed wrinkled and raisin-like appearance. Aerosol powder performance test demonstrated that this formulation exhibited excellent emitted dose (ED, 71%), aerodynamic diameter (2 microm), and respirable fraction (RF, 72%). DSC study suggested an indication of initial electrostatic stabilization of SOD by DPPC and sucrose, the following lipid perturbation by SOD, and the formation of an inclusion complex, thus minimizing the individual transition peaks of SOD and DPPC. FT-IR study showed that the major secondary structure of SOD, beta-sheet, was maintained in this formulation. The surface ESCA analysis of this formulation suggested the absence of SOD on the surface region of the powders, indicating that SOD was well surrounded and protected by DPPC and sucrose. Spray drying has been demonstrated to be a feasible process to preserve the activity of SOD in the formulation of DPPC liposomes with sucrose

1: Acta Neuropathol (Berl). 2004 Feb;107(2):149-58. Epub 2003 Nov 27. : Histological evidence of redox system breakdown caused by superoxide dismutase 1 (SOD1) aggregation is common to SOD1-mutated motor neurons in humans and animal models.
Kato S, Saeki Y, Aoki M, Nagai M, Ishigaki A, Itoyama Y, Kato M, Asayama K, Awaya A, Hirano A, Ohama E.
Department of Neuropathology, Institute of Neurological Sciences, Faculty of Medicine, Tottori University, Nishi-cho 36-1, 683-8504, Yonago, Japan,
kato@grape.med.tottori-u.ac.jp

Living cells produce reactive oxygen species (ROSs). To protect themselves from these ROSs, the cells have developed both an antioxidant system containing superoxide dismutase 1 (SOD1) and a redox system including peroxiredoxin2 (Prx2, thioredoxin peroxidase) and glutathione peroxidase1 (GPx1): SOD1 converts superoxide radicals into hydrogen peroxide (H(2)O(2)), and H(2)O(2) is then converted into harmless water (H(2)O) and oxygen (O(2)) by Prx2 and GPx1 that directly regulate the redox system. To clarify the biological significance of the interaction of the redox system (Prx2/GPx1) with SOD1 in SOD1-mutated motor neurons in vivo, we produced an affinity-purified rabbit antibody against Prx2 and investigated the immunohistochemical localization of Prx2 and GPx1 in neuronal Lewy body-like hyaline inclusions (LBHIs) in the spinal cords of familial amyotrophic lateral sclerosis (FALS) patients with a two-base pair deletion at codon 126 and an Ala-->Val substitution at codon 4 in the SOD1 gene, as well as in transgenic rats expressing human SOD1 with H46R and G93A mutations. The LBHIs in motor neurons from the SOD1-mutated FALS patients and transgenic rats showed identical immunoreactivities for Prx2 and GPx1: the reaction product deposits with the antibodies against Prx2 and GPx1 were localized in the LBHIs. In addition, the localizations of the immunoreactivities for SOD1 and Prx2/GPx1 were similar in the inclusions: the co-aggregation of Prx2/GPx1 with SOD1 in neuronal LBHIs in mutant SOD1-related FALS patients and transgenic rats was evident. Based on the fact that Prx2/GPx1 directly regulates the redox system, such co-aggregation of Prx2/GPx1 with SOD1 in neuronal LBHIs may lead to the breakdown of the redox system itself, thereby amplifying the mutant SOD1-mediated toxicity in mutant SOD1-linked FALS patients and transgenic rats expressing human mutant SOD1.

Biol Trace Elem Res. 2004 Feb;96(1-3):117-24. : Effect of iron supplementation on oxidative stress and antioxidant status in iron-deficiency anemia.
Kurtoglu E, Ugur A, Baltaci AK, Undar L.
Department of Hematology, Medical School, Selcuk University, Konya, Turkey.

This study was designed to measure the effect of iron supplementation on antioxidant status in iron-deficient anemia, including the time for hemoglobin normalization and at the time of filling of iron body stores. The extent of plasma lipid peroxidation was evaluated by measuring the levels of malondialdehyde and glutathione peroxidase (GSH-Px), and the activities of superoxide dismutase (SOD) and catalase in 63 patients with iron-deficiency anemia before and after 6 wk of iron supplementation and at the time when body iron stores are saturated. After 6 wk of iron supplementation, a significant decrease of oxidative stress was observed in the treated subjects relative to controls (p<0.05). No significant differences existed between treated patients at 6 wk and at the end of the study. The erythrocyte levels of catalase, SOD, and GSH-Px were significantly lower in treated patients relative to controls (p<0.05). These levels increased after 6 wk of supplementation (p<0.05) and showed no significant differences with those at the end of the study.

1: Clin Chim Acta. 2004 Feb;340(1-2):229-33. : Antioxidant potential of vitamins A, E and C in modulating oxidative stress in rat brain.
Zaidi SM, Banu N.
Department of Biochemistry, Faculty of Life Sciences, A.M.U. 202002, Aligarh, India

BACKGROUND: Stress is known to affect synaptic plasticity, dendritic morphology and induces neurotoxic damage in humans, probably through generation of free radicals. Both ex vivo antioxidant vitamins and in vivo free radical scavenging enzymes exist. In the present study, restraint stress induced pro-oxidant status of rat brain was evaluated in terms of measurement of glutathione (GSH), lipid peroxidation (thiobarbituric acid reactive substances, TBARS) and free radical scavenging enzymes activities. The efficacy of antioxidant vitamins A, E and C alone and in combination was also evaluated in modulating inherent antioxidant system in stressed rats. METHODS: Rats were treated with vit A, E and C alone (15 mg/kg of body weight) and in combination vitamins (E and C) prior to and after 6 h of restraint stress exposure. Both nonstressed and stressed rats were handled simultaneously. Pro-oxidant status of brain tissue was evaluated by determining the levels of GSH, TBARS and activities of superoxide dismutase (SOD), glutathione-S-transferase (GST) and catalase (CAT). RESULTS: Restraint stress induced a decrease in the level of GSH and the activities of SOD, GST and catalase, while the levels of TBARS were found elevated. Both pre-stress and post-stress vitamin treatments (either alone or combined) resulted in alteration of these parameters towards their controls values with a relative dominance by latter. Vitamin E was found most effective in restoring inherent antioxidant system, no additive effect was observed in combined vitamin treatment as expected. CONCLUSION: Immobilization of rats generated oxidative stress in rat brain, by decreasing the activities of SOD, GST, catalase and glutathione levels, while increasing the lipid peroxidation. Post stress vitamin E treatment was found most effective than vitamins A and C in enhancing the levels of glutathione and activities of SOD, GST and catalase and decreasing lipid peroxidation. Thus vitamin E can be given as a nutritional supplement for scavenging free radical generated in the brain tissues in order to reduce oxidative stress.

: J Nutr Biochem. 2003 Nov;14(11):656-62. : Beta-carotene supplementation decreases leukocyte superoxide dismutase activity and serum glutathione peroxidase concentration in humans.
McGill CR, Green NR, Meadows MC, Gropper SS.
Tropicana Products, Inc., 1001 13th Avenue East, Bradenton, FL 34208, USA.
carla.mcgill@tropicana.com

The effects of a 30 mg/day beta-carotene supplement for 60 days on blood cell and serum antioxidant enzymes and selenium concentrations were examined in healthy adults. Serum beta-carotene concentrations increased significantly (P < 0.05) in response to supplementation. Forty percent of subjects exhibited hypercarotenemia of the skin after 30 days. There were no changes in the activity of red blood cell or leukocyte catalase activity, red blood cell copper,zinc-dependent superoxide dismutase activity or serum myeloperoxidase concentration in response to beta-carotene supplementation. Leukocyte superoxide dismutase activity decreased significantly (P < 0.05) at 30 and 60 days compared to baseline. Serum glutathione peroxidase concentration decreased significantly (P < 0.05) between baseline and days 45 and 60 of supplementation. Serum selenium and blood hemoglobin concentrations did not change during the study. Supplemental beta-carotene may alter the antioxidant capacity of plasma and/or blood cells in vivo