Cystatin C (CysC) is a major protein component of Bunina bodies, which are a pathological hallmark observed in the remaining motor neurons of patients with amyotrophic lateral sclerosis (ALS). Dominant mutations in the SOD1 gene, encoding Cu/Zn superoxide dismutase (SOD1), are causative for a subset of inherited ALS cases. Our previous study showed that CysC exerts a neuroprotective effect against mutant SOD1‐mediated toxicity in vitro; however, in vivo evidence of the beneficial effects mediated by CysC remains obscure. Here we examined the therapeutic potential of recombinant human CysC in vivo using a mouse model of ALS in which the ALS‐linked mutated SOD1 gene is expressed (SOD1G93A mice). Intracerebroventricular administration of CysC during the early symptomatic SOD1G93A mice extended their survival times. Administered CysC was predominantly distributed in ventral horn neurons including motor neurons, and induced autophagy through AMP‐activated kinase activation to reduce the amount of insoluble mutant SOD1 species. Moreover, PGC‐1α, a disease modifier of ALS, was restored by CysC through AMP‐activated kinase activation. Finally, the administration of CysC also promoted aggregation of CysC in motor neurons, which is similar to Bunina bodies. Taken together, our findings suggest that CysC represents a promising therapeutic candidate for ALS.
In this study, we have analyzed superoxide dismutase (SOD), ascorbate peroxidase (APX) and glutathione reductase (GR) activities, biomass accumulation and chlorophyll‐a content in the Arthrospira platensis ‐M2 strain grown at different concentrations of zinc (Zn), tin (Sn) and mercury (Hg). We found that there is a close relationship between chlorophyll‐a content and biomass accumulation in A. platensis ‐M2 strain as a result of Zn, Sn and Hg exposures. Sn was found to be the most toxic heavy metal among others because of the continious inhibition of both biomass and chlorophyll‐a accumulation at 500 and 1000 μg mL?1 concentrations after the third day of the study, while they represented continuous increases at each Zn and Hg concentration over 7 days. Lower concentrations of Zn and Sn stimulate SOD and GR activities remarkably, probably due to oxidative stress caused by heavy metal toxicity. APX activity was significantly lowered by higher concentrations of the three metals used in this study. Our results suggest that higher heavy metal concentrations inhibited SOD, APX and GR activities but biomass and chlorophyll‐a accumulation endured in a time‐dependent manner, possibly due to some different defence mechanisms, which remain to be investigated. 相似文献
Superoxide dismutase (SOD, EC 1.15.1.1) is an important metal-containing antioxidant enzyme that provides the first line of defense against toxic superoxide radicals by catalyzing their dismutation to oxygen and hydrogen peroxide. SOD is classified into four metalloprotein isoforms, namely, Cu/Zn SOD, Mn SOD, Ni SOD and Fe SOD. The structural models of soybean SOD isoforms have not yet been solved. In this study, we describe structural models for soybean Cu/Zn SOD, Mn SOD and Fe SOD and provide insights into the molecular function of this metal-binding enzyme in improving tolerance to oxidative stress in plants. 相似文献
The free radical scavenging activity of the Japanese herbal medicine, Toki-Shakuyaku-San (TJ-23; TSUMURA & Co., Tokyo, Japan),
was examined using electron spin resonance (ESR) spectrometry. TJ-23 scavenged 1,1-diphenyl-2-picrylhydrazyl radicals (DPPH),
superoxide (O2−), and hydroxyl radicals (·OH) dose-dependently. It also diminished carbon centered radicals (·C) generated by oxidative stress
and inhibited thiobarbituric acid-reactive substances (TBARS) formation in mouse cortex homogenate. In addition, the effect
of TJ-23 on the concentration of neurotransmitters and TBARS formation, and superoxide dismutase (SOD) activity in the cortex,
hippocampus and striatum of the aged rat brain was studied. The concentrations of the metabolites of monoamines, glutamate
and glutamine were decreased by 4 weeks of oral administration of TJ-23. The SOD activity of mitochondrial fraction was increased
and TBARS formation was significantly suppressed. These results suggest that TJ-23 has an antioxidant action and would have
a prophylactic effect against free radical-mediated neurological diseases associated with aging. 相似文献
Oxidative stress is a major factor in aging processes. Superoxide dismutase 3 (SOD3) plays a key role in the protection of extracellular oxidative stress. Missense mutations in SOD3 have been described to be associated with the occurrence of pulmonary, cardiovascular, and neoplastic diseases. This study aims to analyze the effects of missense mutations on the SOD3 structure and function by modeling a complete SOD3 structure as well as analyzing the differences between the wild-types and mutants using computational simulations. Here, ten algorithms were used to predict the structural and functional effects of missense mutations. A complete model of SOD3 protein was made by ab initio and comparative modeling using the Rosetta algorithm and validated by PROCHECK, Verify 3D, QMEAN, and ProSa. Molecular dynamics (MD) simulations were performed and analyzed using the GROMACS package. The deleterious potential of the A58T and R231G mutants was not predicted by the majority of the used algorithms. The analyzed mutations were predicted as destabilizing by at least one algorithm. The MD analyses indicated that protein flexibility may be increased by all of the analyzed mutations, while the protein-ligand stability may be decreased. They also suggested that the variants A91T and R231G increase the overall dimensions of SOD3 and decrease its accessible surface area. Our findings, therefore, indicated that the analyzed mutations could affect the protein structure and its ability to interact with other molecules, which may be related to the functional impairment of SOD3 upon A58T and R231G mutations, as well as their involvement in pathologies. 相似文献