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The goal of this study was to test the role cellular senescence plays in the increased inflammation, chronic liver disease, and hepatocellular carcinoma seen in mice null for Cu/Zn‐Superoxide dismutase (Sod1KO). To inhibit senescence, wildtype (WT) and Sod1KO mice were given the senolytics, dasatinib, and quercetin (D + Q) at 6 months of age when the Sod1KO mice begin exhibiting signs of accelerated aging. Seven months of D + Q treatment reduced the expression of p16 in the livers of Sod1KO mice to WT levels and the expression of several senescence‐associated secretory phenotype factors (IL‐6, IL‐1β, CXCL‐1, and GDF‐15). D + Q treatment also reduced markers of inflammation in livers of the Sod1KO mice, for example, cytokines, chemokines, macrophage levels, and Kupffer cell clusters. D + Q treatment had no effect on various markers of liver fibrosis in the Sod1KO mice but reduced the expression of genes involved in liver cancer and dramatically reduced the incidence of hepatocellular carcinoma. Surprisingly, D + Q also reduced markers of necroptosis (phosphorylated and oligomerized MLKL) in the Sod1KO mice to WT levels. We also found that inhibiting necroptosis in the Sod1KO mice with necrostatin‐1s reduced the markers of cellular senescence (p16, p21, and p53). Our study suggests that an interaction occurs between cellular senescence and necroptosis in the liver of Sod1KO mice. We propose that these two cell fates interact through a positive feedback loop resulting in a cycle amplifying both cellular senescence and necroptosis leading to inflammaging and age‐associated pathology in the Sod1KO mice. [ABSTRACT FROM AUTHOR]

Cu/Zn superoxide dismutase (SOD1) is a frontline antioxidant enzyme catalysing superoxide breakdown and is important for most forms of eukaryotic life. The evolution of aerobic respiration by mitochondria increased cellular production of superoxide, resulting in an increased reliance upon SOD1. Consistent with the importance of SOD1 for cellular health, many human diseases of the central nervous system involve perturbations in SOD1 biology. But far from providing a simple demonstration of how disease arises from SOD1 loss‐of‐function, attempts to elucidate pathways by which atypical SOD1 biology leads to neurodegeneration have revealed unexpectedly complex molecular characteristics delineating healthy, functional SOD1 protein from that which likely contributes to central nervous system disease. This review summarises current understanding of SOD1 biology from SOD1 genetics through to protein function and stability. [ABSTRACT FROM AUTHOR]

Mice deficient in the antioxidant enzyme Cu/Zn-superoxide dismutase (Sod1 −/− or Sod1 KO mice) have increased oxidative stress, show accelerated aging and develop spontaneous hepatocellular carcinoma (HCC) with age. Similar to humans, HCC development in Sod1 KO mice progresses from non-alcoholic fatty liver disease (NAFLD) to non-alcoholic steatohepatitis (NASH) with fibrosis, which eventually progresses to HCC. Oxidative stress plays a role in NAFLD to NASH progression, and liver inflammation is the main mechanism that drives the disease progression from NASH to fibrosis. Because necroptosis is a major source of inflammation, we tested the hypothesis that increased necroptosis in the liver plays a role in increased inflammation and fibrosis in Sod1 KO mice. Phosphorylation of MLKL (P -MLKL), a well-accepted marker of necroptosis, and expression of MLKL protein were significantly increased in the livers of Sod1 KO mice compared to wild type (WT) mice indicating increased necroptosis. Similarly, phosphorylation of RIPK3 and RIPK3 protein levels were also significantly increased. Markers of pro-inflammatory M1 macrophages, NLRP3 inflammasome, and transcript levels of pro-inflammatory cytokines and chemokines, e.g., TNFα, IL-6, IL-1β, and Ccl2 that are associated with human NASH, were significantly increased. Expression of antioxidant enzymes and heat shock proteins, and markers of fibrosis and oncogenic transcription factor STAT3 were also upregulated and autophagy was downregulated in the livers of Sod1 KO mice. Short term treatment of Sod1 KO mice with necrostatin-1s (Nec-1s), a necroptosis inhibitor, reversed these conditions. Our data show for the first time that necroptosis-mediated inflammation contributes to fibrosis in a mouse model of increased oxidative stress and accelerated aging, that also exhibits progressive HCC development. • Inflammation and necroptosis are increased in the livers of Sod1 KO mice, a mouse model of increased oxidative stress. • Blocking necroptosis reduced expression of proinflammatory cytokines in livers of Sod1 KO mice. • Blocking necroptosis reduced fibrosis and activation of oncogenic transcription factor STAT3 in the livers of Sod1 KO mice. • Necroptosis-mediated inflammation play a role in chronic liver disease in Sod1 KO mice. [ABSTRACT FROM AUTHOR]

• 6-Deoxyjacareubin suppressed hypoxia-induced cell death via non-apoptotic pathway. • Early 6-deoxyjacareubin administration prolonged survival time in familial ALS model. • 6-Deoxyjacareubin attenuates motor neuron loss and glial activation. • 6-Deoxyjacareubin may be a therapeutic strategy for hypoxia-related neurodegeneration. The central nervous system (CNS) uses a significant amount of oxygen for energy production. Decreased oxygen supply due to impaired blood supply critically damages the CNS. As chronic hypoxic conditions have diverse effects via the excessive production of reactive oxygen species, protection from hypoxic damage is important for cell survival. Recent studies have revealed that various markers of hypoxia are altered in age-related neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), indicating the involvement of hypoxia. However, therapeutic strategies targeting hypoxia-induced pathways in ALS have not been developed yet. We previously screened small-molecule compounds that inhibit hypoxia-induced cell death and identified 6-deoxyjacareubin. We hypothesized that the modulation of hypoxia signaling by 6-deoxyjacareubin might protect motor neurons in ALS. Here, we show that 6-deoxyjacareubin indeed ameliorates neurodegeneration in a mouse model of familial ALS. Administration of 6-deoxyjacareubin to this familial ALS model significantly attenuated disease progression and improved locomotor dysfunction. We also found that 6-deoxyjacareubin reduced motor neuron loss and glial activation. Our results indicate that 6-deoxyjacareubin might serve as a potential therapeutic tool for ALS. Moreover, these results suggest that modulation of hypoxia signaling pathways provides a promising strategy to develop therapies for other types of neurodegenerative diseases also characterized by hypoxia. [ABSTRACT FROM AUTHOR]

Cu/Zn Superoxide Dismutase (Sod1) catalyzes the disproportionation of cytotoxic superoxide radicals (O 2 •-) into oxygen (O 2) and hydrogen peroxide (H 2 O 2), a key signaling molecule. In Saccharomyces cerevisiae , we previously discovered that Sod1 participates in an H 2 O 2 -mediated redox signaling circuit that links nutrient availability to the control of energy metabolism. In response to glucose and O 2 , Sod1-derived H 2 O 2 stabilizes a pair of conserved plasma membrane kinases - yeast casein kinase 1 and 2 (Yck1/2) - that signal glycolytic growth and the repression of respiration. The Yck1/2 homolog in humans, casein kinase 1-γ (CK1γ), is an integral component of the Wingless and Int-1 (Wnt) signaling pathway, which is essential for regulating cell fate and proliferation in early development and adult tissue and is dysregulated in many cancers. Herein, we establish the conservation of the SOD1/YCK1 redox signaling axis in humans by finding that SOD1 regulates CK1γ expression in human embryonic kidney 293 (HEK293) cells and is required for canonical Wnt signaling and Wnt-dependent cell proliferation. • Cu/Zn Superoxide Dismutase (Sod1) is a well conserved and abundant antioxidant enzyme. • Sod1 plays important roles in redox signaling due to its production of H 2 O 2. • Sod1 regulates the canonical Wnt signaling pathway. [ABSTRACT FROM AUTHOR]

Superoxide dismutase is widespread in the human body, including skin and its appendages. Here, we focus on human skin copper/zinc superoxide dismutase, the enzyme that protects skin and its appendages against reactive oxygen species. Human skin copper/zinc superoxide dismutase resides in the cytoplasm of keratinocytes, where up to 90% of cellular reactive oxygen species is produced. Factors other than cell type, such as gender, age and diseased state influence its location in skin tissues. We review current knowledge of skin copper/zinc superoxide dismutase including recent studies in an attempt to contribute to solving the question of its remaining unexplained functions. The research described here may be applicable to pathologies associated with oxidative stress. However, recent studies on copper/zinc superoxide dismutase in yeast reveal that its predominant function may be in signaling pathways rather than in scavenging superoxide ions. If confirmed in the skin, novel approaches might be developed to unravel the enzyme's remaining mysteries.

Quercetin (QE; 3,5,7,3′,4′-pentahydroxyflavone), a well-known flavonoid, has been shown to prevent against neurodegenerative disorders and ischemic insults. However, few studies are reported regarding the neuroprotective mechanisms of QE after ischemic insults. Therefore, in this study, we investigated the effects of QE on ischemic injury and the expression of antioxidant enzymes in the hippocampal CA1 region of gerbils subjected to 5 minutes of transient cerebral ischemia. QE was pre-treated once daily for 15 days before ischemia. Pretreatment with QE protected hippocampal CA1 pyramidal neurons from ischemic injury, which was confirmed by neuronal nuclear antigen immunohistochemistry and Fluoro-Jade B histofluorescence staining. In addition, pretreatment with QE significantly increased the expression levels of endogenous antioxidant enzymes Cu/Zn superoxide dismutase, Mn superoxide dismutase, catalase and glutathione peroxidase in the hippocampal CA1 pyramidal neurons of animals with ischemic injury. These findings demonstrate that pretreated QE displayed strong neuroprotective effects against transient cerebral ischemia by increasing the expression of antioxidant enzymes.

Copper (Cu) and zinc (Zn) are involved in inflammatory process. This study was to investigate the clinical significance of Cu and Zn homeostasis alterations in acute appendicitis (AA). One hundred twenty-two AA patients and 102 healthy controls were enrolled in this study. Of which, 85 patients' appendixes were collected after appendectomy. Another six appendixes from colon cancer patients were collected as tissue controls. The contents of Cu and Zn in serum or appendix were detected, and the Cu to Zn ratio (CZr) was calculated. The concentrations of serum ceruloplasmin (CP), Cu/Zn superoxide dismutase (SOD1), interleukin-6 (IL-6), and interleukin-22 in serum were measured, as well as the activity of CP and SOD1. The serum Zn concentration and SOD1 activity, appendix contents of Cu and Zn significantly decreased in AA patients, compared with those of controls, while serum CZr, concentrations of CP, SOD1, and IL-6, as well as CP activity increased significantly in AA patients. Additionally, serum concentrations of Zn, CP, CZr, or SOD1 activity varied in different pathological types of AA. Indicators such as serum SOD1 activity might serve as predictors for pathological classification before surgery. The serum Zn and CZr may be helpful for diagnosis of pure AA. The Cu and Zn homeostasis was altered in AA patients, which might contribute to inflammatory process of AA. [ABSTRACT FROM AUTHOR]

Abstract In the parasitoid/polydnavirus/host system, polydnaviruses protect larva development in the host hemocoel by suppressing the host immune response. However, the negative effects on the parasitoid and the strategy of the parasitoid to deal with this disadvantage are still unknown. Microplitis bicoloratus bracovirus induces granulocyte apoptosis to suppress immune responses, resulting in an apoptotic haemolymph environment in which immature M. bicoloratus larva develop. Here, we determined the transcriptional profiles of immature M. bicoloratus across five time-points throughout the immature developmental process from egg to third instar. Dynamic gene expression pattern analysis revealed clear rapid changes in gene expression characteristic of each developmental stage, indicating faster sequential unambiguous functional division during development. Combined with the proteome of the host haemolymph, immature parasitoids likely secreted a Cu/Zn superoxide dismutase to reduce reactive oxygen species generation by symbiotic bracovirus. These data established a basis for further studies of parasitoid/host interactions and identified a novel positive self-protection mechanism for the parasitoid. Highlights • Immature parasitoids secreted a Cu/ZnSOD. • Cu/ZnSOD reduces ROS triggered by bracovirus. • A positive self-protection mechanism. [ABSTRACT FROM AUTHOR]

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Skeletal muscle ageing is characterised by atrophy, a deficit in specific force generation, increased susceptibility to injury, and incomplete recovery after severe damage. The hypothesis that increased generation of reactive oxygen species (ROS) in vivo plays a key role in the ageing process has been extensively studied, but remains controversial. Skeletal muscle generates ROS at rest and during exercise. ROS can cause oxidative damage particularly to proteins. Indeed, products of oxidative damage accumulate in skeletal muscle during ageing and the ability of muscle cells to respond to increased ROS becomes defective. The aim of this review is to examine the evidence that ROS manipulation in peripheral nerves and/or muscle modifies mechanisms of proteostasis in skeletal muscle and plays a key role in initiating sarcopenia. [ABSTRACT FROM AUTHOR]

Cu/Zn superoxide dismutase (SOD) and catalase (CAT) cDNAs from the polychaete Perinereis aibuhitensis were cloned and characterized in order to investigate the relationship between crude oil exposure and stress response in this worm. The full length of PaSOD was 870 bp and PaCAT was 1967 bp encoding 150 and 506 amino acids, respectively. Gene expression and enzyme activity of Cu/Zn SOD and CAT in response to crude oil contaminated soil (500, 1500, and 3000 mg/kg) were measured. The results showed that expression of the CAT gene and enzyme activity in P. aibuhitensis was positively correlated to the concentration of crude oil and reached a maximum at 15 days of exposure to 3000 mg/kg crude oil. The expression of the SOD gene and enzyme activity of SOD in P. aibuhitensis also increased during exposure to crude oil and reached a maximum at 10 days of exposure to 3000 mg/kg crude oil. These results indicated that SOD and CAT are important for maintaining the balance of cellular metabolism and protecting P. aibuhitensis from crude oil toxicity. [ABSTRACT FROM AUTHOR]

Toxicity of HIV-1 envelope glycoprotein (gp120) for substantia nigra (SN) neurons may contribute to the Parkinsonian manifestations often seen in HIV-1-associated dementia (HAD). We studied the neurotoxicity of gp120 for dopaminergic neurons and potential neuroprotection by antioxidant gene delivery. Rats were injected stereotaxically into their caudate-putamen (CP); CP and (substantia nigra) SN neuron loss was quantified. The area of neuron loss extended several millimeters from the injection site, approximately 35% of the CP area. SN neurons, outside of this area of direct neurotoxicity, were also severely affected. Dopaminergic SN neurons (expressing tyrosine hydroxylase, TH, in the SN and dopamine transporter, DAT, in the CP) were mostly affected: intra-CP gp120 caused approximately 50% DAT+ SN neuron loss. Prior intra-CP gene delivery of Cu/Zn superoxide dismutase (SOD1) or glutathione peroxidase (GPx1) protected SN neurons from intra-CP gp120. Thus, SN dopaminergic neurons are highly sensitive to HIV-1 gp120-induced neurotoxicity, and antioxidant gene delivery, even at a distance, is protective.

Mutations in Cu/Zn superoxide dismutase (SOD1) cause autosomal dominant amyotrophic lateral sclerosis (ALS), a devastating neurodegenerative disease with no effective treatment. Despite ample evidence indicating involvement of mutation-induced SOD1 protein misfolding and aggregation in ALS pathogenesis, the molecular mechanisms that control cellular management of misfolded, aggregation-prone SOD1 mutant proteins remain unclear. Here, we report that parkin, an E3 ubiquitin-protein ligase which is linked to Parkinson's disease, is a novel regulator of cellular defense against toxicity induced by ALS-associated SOD1 mutant proteins. We find that parkin mediates K63-linked polyubiquitination of SOD1 mutants in cooperation with the UbcH13/Uev1a E2 enzyme and promotes degradation of these misfolded SOD1 proteins by the autophagy-lysosome system. In response to strong proteotoxic stress associated with proteasome impairment, parkin promotes sequestration of misfolded and aggregated SOD1 proteins to form perinuclear aggresomes, regulates positioning of lysosomes around misfolded SOD1 aggresomes, and facilitates aggresome clearance by autophagy. Our findings reveal parkin-mediated cytoprotective mechanisms against misfolded SOD1 toxicity and suggest that enhancing parkin-mediated cytoprotection may provide a novel therapeutic strategy for treating ALS. [ABSTRACT FROM AUTHOR]

Defects in energy metabolism are potential pathogenic mechanisms in amyotrophic lateral sclerosis (ALS), a rapidly fatal disease with no cure. The mechanisms through which this occurs remain elusive and their understanding may prove therapeutically useful. We used metabolomics and stable isotope tracers to examine metabolic changes in a well-characterized cell model of familial ALS, the motor neuronal NSC-34 line stably expressing human wild-type Cu/Zn superoxide dismutase (wtSOD1) or mutant G93A (G93ASOD1). Our findings indicate that wt and G93ASOD1 expression both enhanced glucose metabolism under serum deprivation. However, in wtSOD1 cells, this phenotype increased supply of amino acids for protein and glutathione synthesis, while in G93ASOD1 cells it was associated with death, aerobic glycolysis, and a broad dysregulation of amino acid homeostasis. Aerobic glycolysis was mainly due to induction of pyruvate dehydrogenase kinase 1. Our study thus provides novel insight into the role of deranged energy metabolism as a cause of poor adaptation to stress and a promoter of neural cell damage in the presence of mutant SOD1. Furthermore, the metabolic alterations we report may help explain why mitochondrial dysfunction and impairment of the endoplasmic reticulum stress response are frequently seen in ALS. [ABSTRACT FROM AUTHOR]

Autophagy-linked FYVE (Alfy) is a protein implicated in the selective degradation of aggregated proteins. In our present study, we found that Alfy was recruited into the aggregated G93A-SOD1 in transgenic mice with amyotrophic lateral sclerosis (ALS). We demonstrated that Alfy overexpression could decrease the expression of mutant proteins via the autophagosome-lysosome pathway, and thereby, the toxicity of mutant proteins was reduced. The clearance of the mutant proteins in NSC34 cells was significantly inhibited in an Alfy knockdown cellular model. We therefore deduced that Alfy translocalization likely is involved in the pathogenesis of ALS. Alfy may be developed into a useful target for ALS therapy. [ABSTRACT FROM AUTHOR]

Caragana is a native desert shrub with high forage values and stress tolerance, as well as sand-fixing capabilities. Some Caragana species, including C. korshinskii, C. microphylla, and C. intermedia, are commonly used for vegetation restoration programs in the Loess Plateau region of northwestern China and are known to have ecological benefits and high commercial value. In this study, full-length sequences of Cu/Zn-SOD genes were isolated from three Caragana species using degenerate polymerase chain reaction (PCR) and rapid amplification of cDNA ends (RACE) techniques, and their expression under drought stress conditions were investigated. The cloned SOD cDNAs contained a predicted open reading frame (ORF) of 459 bp encoding a polypeptide of 152 amino acids with a theoretical molecular weight of 15.2 kD. Cu/Zn-SOD cDNA of C. korshinskii and C. intermedia shared 100% sequence identity, implying a close relationship. A 24-bp specific sequence was found in the 3-UTR region of C. microphylla Cu/Zn-SOD cDNA, and reverse transcription RT-PCR and genomic PCR confirmed the feasibility of the 24-bp sequence as a DNA marker for rapid variety identification of C. microphylla. RT-PCR revealed that the expression of the Caragana Cu/Zn SOD genes was induced by PEG-simulated drought stress and ABA. The three Caragana Cu/Zn-SOD genes showed similar expression patterns, and no significant differences in transcriptional level were observed among the three genes. These results increase our understanding of the molecular mechanism of drought tolerance and can be used to improve vegetation restoration programs of Caragana plants. [ABSTRACT FROM AUTHOR]

Highlights: [•] E2 decreases SOD1 and Ape1 mRNA and protein expression in ovariectomized female mice. [•] E2 increases two markers of oxidative stress, lipid peroxidation and protein carbonylation. [•] Long term E2 treatment may disrupt ROS regulation and play a role in endometrial carcinogenesis. [ABSTRACT FROM AUTHOR]

S. Yamashita, E. Kimura, N. Tawara, H. Sakaguchi, T. Nakama, Y. Maeda, T. Hirano, M. Uchino and Y. Ando (2013) Neuropathology and Applied Neurobiology 39, 406-416 Optineurin is potentially associated with TDP-43 and involved in the pathogenesis of inclusion body myositis Aims: Increasing evidences suggest a similarity in the pathophysiological mechanisms of neuronal cell death in amyotrophic lateral sclerosis (ALS) and myofibre degeneration in sporadic inclusion body myositis (sIBM). The aim of this study is to elucidate the involvement of ALS-causing proteins in the pathophysiological mechanisms in sIBM. Methods: Skeletal muscle biopsy specimens of five patients with sIBM, two with oculopharyngeal muscular dystrophy (OPMD), three with polymyositis (PM), three with dermatomyositis (DM), three with neurogenic muscular atrophy, and three healthy control subjects were examined. We analysed the expression and localization of familial ALS-causing proteins, including transactive response DNA binding protein-43 (TDP-43), fused in sarcoma/translocated in liposarcoma (FUS/TLS), Cu/Zn superoxide dismutase (SOD1) and optineurin (OPTN) by immunohistochemistry. Results: TDP-43, OPTN and, to a lesser extent, FUS/TLS were more frequently accumulated in the cytoplasm in patients with sIBM and OPMD than in patients with PM, DM, neurogenic muscular atrophy, or healthy control subjects. SOD1 was accumulated in a small percentage of myofibres in patients with sIBM and OPMD, and to a very small extent in patients with PM and DM. Confocal microscopy imaging showed that TDP-43 proteins more often colocalized with OPTN than with FUS/TLS, p62 and phosphorylated Tau. Conclusions: These findings suggest that OPTN in cooperation with TDP-43 might be involved in the pathophysiological mechanisms of skeletal muscular degeneration in myopathy with rimmed vacuoles. Further investigation into these mechanisms is therefore warranted. [ABSTRACT FROM AUTHOR]

Abstract: Antioxidant defense is crucial in restoring cellular redox homeostasis. Recent findings have suggested that oxidative stress plays pivotal roles in the pathogenesis of many neurodegenerative diseases. Thus, an anti-oxidative stress remedy might be a promising means for the treatment of such disorders. In this study, we employed a novel ligand-based virtual screening system and identified a novel small molecule, N-(4-(2-pyridyl)(1,3-thiazol-2-yl))-2-(2,4,6-trimethylphenoxy) acetamide (CPN-9), which selectively suppressed oxidative stress-induced cell death in a cell-type-independent manner. CPN-9 upregulates NF-E2-related factor 2 (Nrf2), a key transcriptional regulator of the expression of phase II detoxification enzymes and antioxidant proteins, and Nrf2-regulated factors such as heme oxygenase-1 (HO-1), NAD(P)H quinone oxidoreductase 1 (NQO1), and glutamate–cysteine ligase modifier subunit (GCLM). The CPN-9-mediated upregulation of HO-1, NQO1, and GCLM was abolished by Nrf2 knockdown. Moreover, the antioxidant N-acetylcysteine reduced the protective effect of CPN-9 against oxidative stress-induced cell death with concomitant diminishing of Nrf2 nuclear translocation. These results indicate that CPN-9 exerts its activity via the reactive oxygen species-dependent activation of the Nrf2 signaling pathway in cultured cells. It is noteworthy that the postonset systemic administration of CPN-9 to a transgenic ALS mouse model carrying the H46R mutation in the human Cu/Zn superoxide dismutase (SOD1) gene sustained motor functions and delayed disease progression after onset. Collectively, CPN-9 is a novel Nrf2 activator and a neuroprotective candidate for the treatment of neurodegenerative diseases, including ALS. [Copyright &y& Elsevier]

Abstract: Aims: The study investigated the effect of chronic kidney disease (CKD) and renal replacement therapy on diabetes mellitus-mediated alterations in antioxidative defence and in soluble adhesion molecules (sCAMs). Methods: We assessed plasma Cu/Zn superoxide dismutase (Cu/Zn SOD) and sCAMs (sICAM-1, sVCAM-1) concentrations by ELISA in diabetic and non-diabetic patients on hemodialysis (HD), continuous ambulatory peritoneal dialysis (CAPD) and on conservative treatment. Results: All studied parameters were higher in diabetic patients when compared to non-diabetics CKD patients. Cu/Zn SOD and sVCAM-1 were lower in diabetic patients on HD and on CAPD relative to their non-diabetic counterparts. In contrary, sICAM-1 level was grown up in dialyzed diabetic patients relative to the non-diabetic patients. The positive association was between Cu/Zn SOD and sVCAM-1 in each studied group. The inverse relationship was between glycemia and these parameters in CAPD, whereas the positive correlation was observed between glycemia and sICAM-1. Conclusions: The coexistence of diabetes mellitus is the important factor for the elevation both antioxidant defence as well as sCAMs in CKD patients. The inception of dialysis treatment can affect Cu/Zn SOD and sVCAM-1 but not sICAM-1 levels in diabetics. Moreover, these data suggest that both antioxidative defence and sCAMs could be regulated in different ways by glycemia. [Copyright &y& Elsevier]

Abstract: We reported recently that non-phosphorylated neurofilaments (NF)-positive neurons were more sensitive to the growth inhibitory effects of Cu/Zn superoxide dismutase (SOD1) than phosphorylated NF-positive neurons. The findings suggested that non-phosphorylated NF-positive neurons, presumed to represent spinal motor neurons, are more vulnerable to oxidative stress than other neurons, and thus explain in part the selective degeneration of motor neurons in amyotrophic lateral sclerosis. The present investigation is an extension to our previous study and examined the neurite growth process in the presence of diethyldithiocarbamate (DDC), an SOD1 inhibitor. Non-phosphorylated NF, representing spinal motor neurons, and phosphorylated NF, representing other spinal neurons, were stained with SMI-32 and SMI-31 antibodies, respectively. The distribution histogram of neurite length after treatment with 0nM DDC (control) for 72h appeared flatter compared with that of 24h. Although the addition of DDC (1nM, 10nM, 100nM, or 1000nM) to the culture medium for 72h shifted the histogram of neurite length to a shorter range in a concentration-dependent manner, the neurite of SMI-31-immunoreactive neurons grew under DDC. On the other hand, DDC-treatment for 72h altered the neurite growth of SMI-32-immunoreactive neurons compared with that for 24-h. The results suggest that SOD1 inhibition, representing accumulation of endogenous oxidative stress, suppresses neurite growth of spinal motor neurons, and that the growth of spinal motor neurons is more sensitive to oxidative stress than other types of neurons. [Copyright &y& Elsevier]

Single-nucleotide polymorphisms (SNPs) in the regulatory regions of human genes and, in particular, TATA boxes can alter the sensitivity to bacterial and viral infections and to drugs used for their treatment. These SNPs are associated with the risk of widespread multifactorial human diseases, such as arthritis, hypertension, cancer, Alzheimer's disease, and others. Interaction of the TATA-binding protein (TBP) with TATA boxes on TATA-containing promoters nucleates the preinitiation complex assemblage, which is the initial stage of transcription regulation. This study considers the change of TBP affinity to the TATA boxes of human MBL, CYP 2A6, SOD1, and TPI genes bearing SNPs associated with autoimmune diseases, cardiovascular diseases, amyotrophic lateral sclerosis, neurodegenerative disorders, hypersensitivity to bacterial infections, etc. In all cases a decrease in the affinity of TBP to TATA-containing oligonucleotides was shown. [ABSTRACT FROM AUTHOR]

Familial amyotrophic lateral sclerosis (FALS) accounts for about 5% of cases of the neurodegenerative disorder ALS. At least 100 Cu/Zn superoxide dismutase (SOD1) genetic mutations have been associated with FALS. We identified a FALS family in China with an atypical clinical phenotype. To investigate the SOD1 gene mutations in this family, five exons of the SOD1 gene from each living patient were amplified by PCR and screened by SSCP and direct DNA sequencing. SSCP analysis demonstrated a mutation in exon 2 of SOD1, and DNA sequencing demonstrated the presence of an insertion mutation in exon 2 that has not been reported previously. The mutant SOD1 gene encodes a truncated protein of 35 amino acid residues compared to the normal SOD1 protein of 153 amino acids. In conclusion, The SOD1 exon 2 mutation is likely to be the etiological factor of ALS in this family. [ABSTRACT FROM AUTHOR]

Mutations in the superoxide dismutase-1 (SOD1) gene have been found in 12-23% of patients with a diagnosis of ALS. Here we describe a large ALS Polish family with a branch in France, carrying a G41S mutation in the SOD1, and characterized by an early onset of the disease and extremely short survival time. The mutation has been initially detected in Italian ALS families with common founder effect. However, in the Polish population the G41S mutation most probably originated from an independent mutation event, as indicated by haplotype analysis. Collected data support the hypothesis that a SOD1 mutation is not the sole factor determining the clinical ALS phenotype. [ABSTRACT FROM AUTHOR]

Matrix metalloproteinases (MMPs) are implicated in diverse processes, such as neuroinflammation, leakiness of the blood-brain barrier (BBB) and direct cellular damage in neurodegenerative and other CNS diseases. Tissue destruction by MMPs is regulated by their endogenous tissue inhibitors (TIMPs). TIMPs prevent excessive MMP-related degradation of extracellular matrix components. In a rat model of human immunodeficiency virus (HIV)-related encephalopathy, we described MMP-2 and MMP-9 upregulation by HIV-1 envelope gp120, probably via gp120-induced reactive oxygen species. Antioxidant gene delivery blunted gp120-induced MMP production. We also studied the effect of gp120 on TIMP-1 and TIMP-2 production. TIMP-1 and TIMP-2 levels increased 6 h after gp120 injection into rat caudate-putamen (CP). TIMP-1 and TIMP-2 colocalized mainly with neurons (92 and 95%, respectively). By 24 h, expression of these protease inhibitors diverged, as TIMP-1 levels remained high but TIMP-2 subsided. Gene delivery of the antioxidant enzymes Cu/Zn superoxide dismutase or glutathione peroxidase into the CP before injecting gp120 there reduced levels of gp120-induced TIMP-1 and TIMP-2, recapitulating the effect of antioxidant enzymes on gp120-induced MMP-2 and MMP-9. A significant correlation was observed between MMP/TIMP upregulation and BBB leakiness. Thus, HIV-1 gp120 upregulated TIMP-1 and TIMP-2 in the CP. Prior antioxidant enzyme treatment mitigated production of these TIMPs, probably by reducing MMP expression. [ABSTRACT FROM AUTHOR]

Abstract: Amyotrophic lateral sclerosis (ALS) is characterized by selective degeneration of motor neurons. The reason why only motor neurons are targeted is unknown. Since ALS has been linked to mutations in Cu/Zn superoxide dismutase (SOD1), oxidative stress is regarded as a major cause of ALS. We hypothesized that motor neurons are more susceptible to oxidative stress than other neurons. To test our hypothesis, we investigated differences in neurite growth between motor and non-motor neurons under SOD1 inhibition. Spinal motor neurons were identified by immunocytochemistry using anti-non-phosphorylated neurofilament (NF) antibody (SMI-32). Other neurons immunoreactive to an antibody against phosphorylated NF (SMI-31) were used as a control. Cultured rat spinal neurons were treated with the SOD1 inhibitor diethyldithiocarbamate (DDC). SMI-32-immunoreactive neurons were more sensitive to the growth inhibitory effects of DDC than SMI-31-immunoreactive neurons. Such inhibition was blocked by the antioxidants, L-ascorbic acid, L-histidine, astaxanthin, α-tocopherol, and β-carotene. The results suggested that spinal motor neurons are more vulnerable to oxidative stress than other neurons, which may explain in part the selective degeneration of motor neurons in ALS. [Copyright &y& Elsevier]

Abstract: Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disease characterized by a selective loss of upper and lower motor neurons. Since oxidative stress plays a crucial role in the progression of motor neuron loss observed in ALS, anti-oxidative agents could be an important therapeutic means for the ALS treatment. We have previously developed a drug screening system allowing the identification of small chemical compounds that upregulate endogenous neuronal apoptosis inhibitory protein (NAIP), an oxidative stress-induced cell death suppressor. Using this system, we identified the dopamine D2 receptor agonist bromocriptine (BRC) as one of NAIP-upregulating compounds. In this study, to prove the efficacy of BRC in ALS, we conducted a set of preclinical studies using a transgenic ALS mouse model carrying the H46R mutation in the human Cu/Zn superoxide dismutase (SOD1) gene ALS(SOD1H46R) by the post-onset administration of BRC. ALS(SOD1H46R) mice receiving BRC showed sustained motor functions and modest prolonged survival after onset. Further, BRC treatment delayed anterior horn cell loss, and reduced the number of reactive astrocytes and the level of inflammatory factors such as inducible nitric oxide synthase (iNOS) and tumor necrosis factor (TNF)-α in the spinal cord of late symptomatic mice. In vitro study showed the reduced level of extracellular TNF-α after lipopolysaccharide (LPS) exposure in BRC-treated mouse astrocytes. BRC-treated ALS(SOD1H46R) mice also showed a reduced level of oxidative damage in the spinal cord. Notably, BRC treatment resulted in an upregulation of anti-oxidative stress genes, activating transcription factor 3 (ATF3) and heme oxygenase-1 (HO-1), and the generation of a glutathione (GSH) in SH-SY5Y cultured neuronal cells in a dopamine receptor-independent manner. These results imply that BRC protects motor neurons from the oxidative injury via suppression of astrogliosis in the spinal cord of ALS(SOD1H46R) mice. Thus, BRC might be a promising therapeutic agent for the treatment of ALS. [Copyright &y& Elsevier]

Abstract: The aim of this study was to investigate the influence of cigarette smoking on the pro/antioxidant balance in pregnant women with intrauterine growth restriction (IUGR). The studies have shown a 2-fold increase of Cd concentration in blood of women with IUGR in labour and a 10-fold increase in smoking pregnant women with IUGR. The increase of malondialdehyde concentration in plasma and 8-hydroxydeoxyguanosine in serum and Cu/Zn superoxide dismutase activity in erythrocyte lysate of pregnants with IUGR, reinforced by smoking, was revealed. We observed a decrease in the concentration of glutathione in blood and glutathione peroxidase activity in plasma and in erythrocyte lysate. A 4-fold higher metallothionein concentration in the plasma of women with IUGR in labour suggests that metallothionein may be one of the IUGR markers. Metallothionein concentration was intensified by smoking up to 7-fold in comparison to the controls. The pro/antioxidant balance during pregnancy is significantly affected by smoking. [Copyright &y& Elsevier]

A gene from Withania somnifera (winter cherry), encoding a highly stable chloroplastic Cu/Zn superoxide dismutase (SOD), was cloned and expressed in Escherichia coli. The recombinant enzyme (specific activity of ~4,200 U mg) was purified and characterized. It retained ~90 and ~70% residual activities after 1 h at 80 and 95°C, respectively. At 95°C, thermal inactivation rate constant ( K) of the enzyme was 2.46 × 10 min and half-life of heat inactivation was 4.68 h. The enzyme was stable against a broad pH range (2.5-11.0). It also showed a high degree of resistance to detergent, ethanol and protease digestion. This recombinant Cu/Zn SOD could therefore have useful applications . [ABSTRACT FROM AUTHOR]

Abstract: Defect of metallothionein-III (MT-III) has been reported to be a contributor to the progression of amyotrophic lateral sclerosis (ALS). We explored the expression and effects of MT-III on the motor neurons of spinal cords of ALS model mice (G93A Cu/Zn superoxide dismutase (SOD-1) mutant-transgenic (Tg) mice) using a retrograde viral delivery system. Once-weekly injection of the adenovirus encoding LacZ or MT-III gene was started at the age of 20 weeks, which was the mean age of ALS onset. Gene expression was detected in the motor neurons of the lumbar spinal cord. At 160 days of age (14 days after injection), the mean numbers of Nissl-stained α neurons were 15.42±5.32, 16.50±1.35, and 24.75±4.01 in 5-μm sections of the lumbar hemispinal cord from the untreated group, LacZ group, and MT-III group, respectively. The mean durations of illness were 15.20±5.30 days, 10.33±4.27 days, and 25.71±7.67 days in the untreated group, LacZ group, and MT-III group, respectively. The mean life spans were 163.20±7.72 days, 159.50±3.27 days, and 178.14±12.97 days in the untreated group, LacZ group, and MT-III group, respectively. We demonstrated that MT-III prevents the loss of motor neurons of ALS model mice and prolongs the life span, even when the administration is started at the time of onset. [Copyright &y& Elsevier]

Abstract: There are controversies regarding pain expression in mentally disabled people, including Down syndrome patients. The aim of this study was to examine neuropathic pain-related behavior and peripheral nerve regeneration in mouse model of Down syndrome. Sciatic nerves of double transgenic mice, overexpressing both amyloid precursor protein (APP) and Cu/Zn superoxide dismutase (SOD1) genes, and FVB/N wild type mice were transected and immediately resutured. Evaluation of autotomy and functional recovery was carried out during 4-week follow-up. We found markedly less severe autotomy in transgenic animals, although the onset of autotomy was significantly delayed in control mice. Interestingly, neuroma formation at the injury site was significantly more prominent in transgenic animals. Sciatic function index outcome was better in transgenic mice than in wild-type group. Histological evaluation revealed no statistically significant differences in the number of GAP-43-positive growth cones and macrophages in the distal stump of the transected nerve between groups. However, in transgenic animals, the regenerating axons were arranged more chaotically. The number of Schwann cells in the distal stump of the transected nerves was significantly lower in transgenic mice. The number of surviving motoneurons was markedly decreased in transgenic group. We measured also the atrophy of denervated muscles and found it decreased in APP/SOD1 overexpressing mice. Taken together, in this model of Down syndrome, we observed increased neuroma formation and decreased autotomy after peripheral nerve injury. Our findings suggest that APP/SOD1 overexpressing mice are less sensitive for neuropathic pain associated with neuroma. [Copyright &y& Elsevier]

Abstract: Glial fibrillary acidic protein (GFAP) is an intermediate filament protein that is highly expressed in reactive astrocytes. Increased production of GFAP is a hallmark of astrogliosis in neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS). However, the physiological and pathological roles of GFAP, particularly in chronic neurodegenerative conditions, remain unclear. To address this issue, we here investigate whether absence of GFAP affects the phenotypic expression of motor neuron disease (MND) using an H46R mutant Cu/Zn superoxide dismutase-expressing mouse model of ALS (SOD1 H46R ). GFAP deficient SOD1 H46R mice showed a significant shorter lifespan than SOD1 H46R littermates. Further, at the end stage of disease, loss of GFAP resulted in increased levels of Vim and Aif1 mRNAs, encoding vimentin and allograft inflammatory factor 1 (AIF1), respectively, in the spinal cord, although no discernible differences in the levels and distribution of these proteins between SOD1 H46R and GFAP-deficient SOD1 H46R mice were observed. These results suggest that loss of GFAP in SOD1 H46R mice marginally accelerates the disease progression by moderately enhancing glial cell activation. Our findings in a mouse model of ALS may have implication that GFAP is not necessary for the initiation of disease, but it rather plays some modulatory roles in the progression of ALS/MND. [Copyright &y& Elsevier]

Abstract: The circadian clock in the brain coordinates the phase of peripheral oscillators that regulate tissue-specific physiological outputs. Here we report that circadian variations in the expression and activity of Cu/Zn superoxide dismutase (SOD1; EC 1.15.1.1) are present in liver homogenates from mice. The SOD1 mRNA expression from wild-type (WT) mice peaked at Zeitgeber Time 9 (ZT9; 9h after lights-on time). While there was no rhythmicity in that from period2 (per2) gene knockout (P2K) mice, the level of SOD1 from per1/per2 double knockout (DKO) mice was significantly elevated at ZT5. The enzyme activity of SOD1 was also rhythmic in the mouse liver. Moreover, the total amount of the SOD1 exhibited a rhythmic oscillation with a peak at ZT9 in the liver from WT mice. We also found that tert-butylhydroperoxide (t-BHP)-induced oxidative damage in both WT and P2K mouse embryonic fibroblast (MEF) cells resulted in the up-regulation of SOD1 levels. Our data suggest that the expression of an important antioxidant enzyme, SOD1, is under circadian clock control and that mice are more susceptible to oxidative stress depending on the time of day. [Copyright &y& Elsevier]

Clinical information of two families with amyotrophic lateral sclerosis (ALS) was studied and a mutation analysis of the SOD1 gene was performed using direct DNA sequencing. Two previously reported mutations of the SOD1 gene, G20T (Cys6Phe substitution), and G255C (Leu84Phe substitution), were identified and cosegregated with the disease in the two families. Patients with a Cys6Phe mutation demonstrated rapid disease progression with severe clinical phenotypes, and the patients with a Leu84Phe mutation had a variety of different clinical phenotypes. This is the third report of SOD1 gene mutations in Mainland Chinese patients with different ALS phenotypes. This supports the hypothesis that the clinical course of ALS may vary depending on the specific genetic mutation. [ABSTRACT FROM AUTHOR]

Abstract: Diallyl trisulfide (DATS) is one of the major constituents in garlic oil and has been documented to transcriptionally activate phase II enzymes. The purpose of this study is to evaluate the effects of DATS in prolonging disease duration and survival in a transgenic mouse model of amyotrophic lateral sclerosis (ALS). SOD1-G93A transgenic mice were randomly divided into DATS-treated group (80mg/kg/d, p.o.) and vehicle-treated group at disease onset stage. Oral administration of DATS beginning at clinical onset stage significantly prolonged disease duration and extended life span for about one week. DATS treatment induced HO-1 and reduced GFAP expression in the lumbar spinal cord of SOD1-G93A transgenic mice. This study indicates that DATS has multifunctional neuroprotective effects in SOD1-G93A transgenic mice. [Copyright &y& Elsevier]

The copper chaperone for superoxide dismutase (CCS) binds to both the β-site AβPP cleaving enzyme (BACE1) and to the neuronal adaptor protein X11α. BACE1 initiates AβPP processing to produce the amyloid-β (Aβ) peptide deposited in the brains of Alzheimer's disease patients. X11α also interacts directly with AβPP to inhibit Aβ production. However, whether CCS affects AβPP processing and Aβ production is not known. Here we show that loss of CCS increases Aβ production in both CCS knockout neurons and CCS siRNA-treated SHSY5Y cells and that this involves increased AβPP processing at the BACE1 site. [ABSTRACT FROM AUTHOR]

J. Neurochem. (2010) 113, 860–870. Mutations in Cu/Zn superoxide dismutase ( SOD1) gene cause familial amyotrophic lateral sclerosis (ALS), which could be attributed to the toxic properties of the misfolded protein, oxidative stress, and mitochondrial dysfunction. DJ-1 – a causative agent of familial Parkinson’s disease PARK7 – is responsible for inducing antioxidative reaction. In this study, we showed the up-regulation of DJ-1 protein levels in mutant SOD1 transgenic mice through the lifespan were observed in the motor neurons. We demonstrated biochemically DJ-1 formed complexes with mutant SOD1 in the cell lysates. Furthermore, DJ-1 over-expression resulted in increased cell viability and reduced cell toxicity in mutant SOD1-transfected neuronal cells, because of improvement in apoptotic pathway and reduction in oxidative stress levels. We also evaluated DJ-1 levels in CSF collected from sporadic ALS patients and controls subjects. The CSF DJ-1 levels were significantly higher in patients with sporadic ALS than in control subjects. These results show that DJ-1 may be associated with sporadic and familial ALS pathogenesis. Therefore, insight into the effects of DJ-1 on mutant SOD1-mediated toxicity may provide a therapeutic advance for the treatment of motor neuron degeneration in ALS. [ABSTRACT FROM AUTHOR]

Amyotrophic lateral sclerosis (ALS) is a conformational disease in which misfolding and aggregation of proteins such as SOD1 (familial ALS) and TDP-43 (sporadic ALS) are central features. The conformations adopted by such proteins within motor neurons in affected patients are not well known. We have developed a novel conformation-specific antibody (USOD) targeted against SOD1 residues 42–48 that specifically recognizes SOD1 in which the beta barrel is unfolded. Use of this antibody, in conjunction with the previously described SEDI antibody that recognizes the SOD1 dimer interface, allows a detailed investigation of the in vivo conformation of SOD1 at the residue-specific level. USOD and SEDI immunohistochemistry of spinal cord sections from ALS cases resulting from SOD1 mutations (A4V and ΔG27/P28) shows that inclusions within remaining motor neurons contain SOD1 with both an unfolded beta barrel and a disrupted dimer interface. Misfolded SOD1 can also be immunoprecipitated from spinal cord extracts of these cases using USOD. However, in ten cases of sporadic ALS, misfolded SOD1 is not detected by either immunohistochemistry or immunoprecipitation. Using the amyloid-specific dyes, Congo Red and Thioflavin S, we find that SOD1-positive inclusions in familial ALS, as well as TDP-43- and ubiquitin-positive inclusions in sporadic ALS, contain non-amyloid protein deposits. We conclude that SOD1 misfolding is not a feature of sporadic ALS, and that both SOD1-ALS and sporadic ALS, rather than being amyloid diseases, are conformational diseases that involve amorphous aggregation of misfolded protein. This knowledge will provide new insights into subcellular events that cause misfolding, aggregation and toxicity. [ABSTRACT FROM AUTHOR]

Abstract: A partial cDNA sequence of a putative Cu/Zn superoxide dismutase (SOD) from Haliotis diversicolor supertexta with abalone juvenile detached syndrome (AJDS) was isolated by suppression subtractive hybridization library screening. The full 988 base pair (bp) abalone Cu/Zn SOD cDNA representing full cDNA coding sequence was obtained by rapid amplification of cDNA ends (RACE), and included a 462-bp open reading frame encoding 154 amino acids, plus 49bp of 5′-, and 477bp of 3′-untranslated region. The coding sequence shared high similarity and identity with known Cu/Zn SODs. The deduced amino acids contained two typical Cu/Zn SOD motifs and the conserved geometry active sites. Moreover, the cysteines involved in dimer formation, and the copper- and zinc-binding sites were conserved. Recombinant abalone Cu/Zn SOD (abSOD) was expressed in Escherichia coli, purified under denaturing conditions, and refolded by direct buffer exchange or gel gradient recovery. The activity of the purified protein was enhanced by 1μM Cu2+ or 1μM Cu2+ plus 1μM Zn2+. The transcription of abSOD was significantly increased in AJDS abalones compared to controls, while protein expression and SOD enzyme activity both decreased significantly, suggesting that SOD may play an important role in AJDS, and that the disease etiology may be related to environmental stress. [Copyright &y& Elsevier]

Abstract: A new thermostable Cu/Zn SOD from a thermotolerant yeast strain Kluyveromyces marxianus NBIMCC 1984 has been purified and characterized. The purification procedure comprises thermal treatment and dialysis, ion-exchange chromatography and chromatofocusing. The methodology is a rapid, efficient and highly specific, generating pure preparation (specific activity 996Umg of protein−1) with a yield of 53%. The purified enzyme is a homodimer with Mw of 34034Da and has high N-terminal homology with other yeasts’ Cu/Zn SOD enzymes. The protein is characterized with some unique features such as—thermostability (t 1/2 at 70°C=30min), pH stability in the alkaline range (7.5–8.5) and resistance to inhibitors and variety of chemicals. These characteristics reveal possibilities for wide practical application of K. marxianus Cu/Zn SOD enzyme. [Copyright &y& Elsevier]

Abstract: Carbon tetrachloride (CCl4) is a well-known model compound for producing chemical hepatic injury. This study investigated the protective effects of the flavonoid luteolin on the CCl4-induced hepatotoxicity in mice. Luteolin dissolved in dimethyl sulfoxide (DMSO) was administered intraperitoneally (i.p.) at 5 or 50mg/kg as a single dose, and once daily for 2 consecutive days. Two hours after the final treatment, the mice were treated with CCl4 (20mg/kg, i.p.). CCl4-induced hepatotoxicity was reduced in a dose- and time-dependent manner, as determined by decreased serum aminotransferase activities and liver histopathology. CCl4 intoxication resulted in an overexpression of heat shock protein gp96 in the mice liver, which was strongly attenuated by luteolin pretreatment. Luteolin has also decreased oxidative stress produced by CCl4, as suggested by improvement in the Cu/Zn superoxide dismutase activity. The effect of luteolin on myeloperoxidase, an indicator of inflammatory cell infiltration, was also investigated. Treatment of the mice with luteolin resulted in a significant decrease in the myeloperoxidase activity. The hepatoprotective effect of luteolin against CCl4 hepatotoxicity was higher in animals pretreated with luteolin for 2 consecutive days. This suggests that the protection might be due to induction of some adaptive mechanisms. The data indicate that luteolin could be effective in protecting mice from the hepatotoxicity produced by CCl4. [Copyright &y& Elsevier]

Abstract: Toxicity of HIV-1 envelope glycoprotein (gp120) for substantia nigra (SN) neurons may contribute to the Parkinsonian manifestations often seen in HIV-1-associated dementia (HAD). We studied the neurotoxicity of gp120 for dopaminergic neurons and potential neuroprotection by antioxidant gene delivery. Rats were injected stereotaxically into their caudate-putamen (CP); CP and (substantia nigra) SN neuron loss was quantified. The area of neuron loss extended several millimeters from the injection site, approximately 35% of the CP area. SN neurons, outside of this area of direct neurotoxicity, were also severely affected. Dopaminergic SN neurons (expressing tyrosine hydroxylase, TH, in the SN and dopamine transporter, DAT, in the CP) were mostly affected: intra-CP gp120 caused approximately 50% DAT+ SN neuron loss. Prior intra-CP gene delivery of Cu/Zn superoxide dismutase (SOD1) or glutathione peroxidase (GPx1) protected SN neurons from intra-CP gp120. Thus, SN dopaminergic neurons are highly sensitive to HIV-1 gp120-induced neurotoxicity, and antioxidant gene delivery, even at a distance, is protective. [Copyright &y& Elsevier]

Abstract: The deep-sea yeast Cryptococcus liquefaciens strain N6 shows high tolerance towards heavy metals, and can grow in the presence of high concentrations of copper ions. Enzymatic analysis indicated that copper ions induced the Cu/Zn superoxide dismutase activity of strain N6 (Cl-SOD1). In this study, the 1.2Å resolution crystal structure of Cl-SOD1 has revealed several significant residue substitutions compared to the other Cu/Zn SODs. In the electrostatic loop, notably, His135 and Pro136 replace the well-conserved linear residues, while Thr133 substitutes a highly conserved glycine. The electrostatic loop has been shown to be involved in the copper uptake process, and these substitutions have caused an inward dragging of the turn region of the loop. As the introduction of proline and abolishment of glycine decrease loop flexibility, this structural reorganization may have helped stabilize the loop conformation, possibly resulting in more efficient copper uptake and a more stabilized copper-bound form. [Copyright &y& Elsevier]

Background/Aim: Oxidative stress is known to be enhanced in hemodialysis patients, and one of its useful markers is plasma copper/zinc superoxide dismutase (Cu/Zn-SOD). The increase in plasma Cu/Zn-SOD can be inhibited by orally administered lipid-soluble vitamin E. We examined the antioxidative effects of water-soluble vitamin C administered orally on Cu/Zn-SOD levels in hemodialysis patients. Methods: Vitamin C was orally administered to 16 maintenance hemodialysis patients before each dialysis session. Doses were increased from 200 to 1,000 mg over 3 months. The levels of plasma vitamin C and Cu/Zn-SOD and its mRNA expression in leukocytes were determined 1, 2, and 3 months after the start of vitamin C administration. Furthermore, the levels of oxidized and reduced forms of plasma vitamin C were determined before the start of vitamin C administration and before and after dialysis at 1,000-mg vitamin C doses. Results: Following oral administration, the plasma levels of vitamin C and its oxidized form were increased. However, significant changes in plasma Cu/Zn-SOD or its mRNA expression in leukocytes were not observed. Conclusion: In maintenance hemodialysis patients, vitamin C administration resulted in a significant increase in the postdialysis level of the oxidized form of vitamin C, which suggested an increase in antioxidant effect. However, water-soluble vitamin C did not significantly suppress Cu/Zn-SOD expression enhancement. Copyright © 2008 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]