Biochemical and Biophysical Research Communications
Regular ArticleStructural Dimorphism in the Mitochondrial Targeting Sequence in the Human Manganese Superoxide Dismutase Gene: A Predictive Evidence for Conformational Change to Influence Mitochondrial Transport and a Study of Allelic Association in Parkinson's Disease
Abstract
Mitochondrial targeting sequence (MTS) has a common property to form an amphiphilic helical structure which is essential for its effective transport of mitochonmdrial protein. Natural polymorphism in human MTS which affects its mitochondrial transport ability has not been reported. Furthermore, no structural polymorphism for manganese superoxide dismutase (MnSOD) gene has been studied in human population. We here identify diallelic polymorphism (Ala-9Val) in the MTS of human MnSOD in a Japanese population. Calculation of a helix forming potential predicted the typical amphiphilic helical structure in -9Ala allele and its disruption in -9Val allele. We here suggest that this mutation may reflect functional polymorphism of mitochondrial transport of human MnSOD. An association study using this polymorphism showed significant allelic deviation for -9Ala allele (12.1% vs. 19.3%) in Parkinson's disease.
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Polycystic Ovary syndrome (PCOS) is a heterogeneous disease, and its pathophysiology is quite complex. Hyperandrogenism, insulin resistance and recently oxidative stress are considered the main causes of initiating and developing the disease, they act synergistically and stimulate each other in a vicious cycle. Our study was aimed at investigation the relationship between polymorphisms in the genes CYP17 (rs743572), SOD2 (rs4880), and CAT (rs1001179) and the risk of PCOS. As well as to establish the relationship of polymorphic markers with the development of oxidative stress and a violation of the hormonal profile of blood serum and follicular fluid in PCOS. Our genotyping analysis showed that polymorphisms in CYP17 (rs743572) and SOD2 (rs4880), but not CAT (rs1001179) might be risk factors for PCOS development, since the presence of at least one mutant allele of rs743572 or rs4880 increases the risk of developing the syndrome. We found an association between LH and estradiol levels in the serum and the polymorphic variants of CYP17 (rs743572) and SOD2 (rs4880), respectively in PCOS patients. Furthermore, our results demonstrate a significant increase in oxidative stress with a decrease in SOD and CAT activity in the follicular fluid of PCOS patients.
The MnSOD Ala16Val single nucleotide polymorphism (SNP) has shown to be associated to risk factors of several metabolic and vascular diseases. However, little is known about interaction between MnSOD Ala16Val SNP in stroke, a frequent neurologic disease that involves clinic manifestations such as motor deficits and spasticity. In this sense, we decided to investigate the relationship between MnSOD Ala16Val SNP with spasticity in stroke and also its influence on interleukin levels, BDNF, and glycolipid parameters. Eighty post-stroke subjects and 80 healthy controls were investigated. We showed a higher spasticity, levels of total cholesterol, LDL, IL-1β, IL-6, and INF-γ in VV post-stroke group. Interesting, we found a correlation between IL-1β levels and spasticity in VV post-stroke. Triglycerides, glucose levels and caspases (1 and 3) activation were significantly higher, as well as BDNF levels were lower in VV and AV post-stroke. DNA damage was higher in post-stroke group. Thus, we can suggest that the V allele has a worse glycolipid profile, which would facilitate changes in neurovascular homeostasis. These events associated with an increase in inflammatory markers and a reduction in BDNF can contribute with the stroke and a worse clinical evolution in relation to spasticity in patients with VV genotype.
Association of GSTO1, GSTO2, GSTP1, GPX1 and SOD2 polymorphism with primary open angle glaucoma
2022, Experimental Eye ResearchIt is becoming increasingly evident that oxidative stress has a supporting role in pathophysiology and progression of primary open angle glaucoma (POAG). The aim of our study was to assess the association between polymorphisms in genes encoding enzymes involved in redox homeostasis, mitochondrial superoxide dismutase (SOD2), glutathione peroxidase (GPX1) and glutathione transferases (GSTs) with susceptibility to POAG. Single nucleotide polymorphisms in GST omega (GSTO1rs4925, GSTO2 rs156697), pi 1 (GSTP1 rs1695), as well as GPX1 (rs1050450) and SOD2 (rs4880) were determined by quantitative polymerase chain reaction (qPCR) in 102 POAG patients and 302 respective controls. The risk for POAG development was noted in carriers of both GSTO2*GG and GSTO1*AA variant genotypes (OR = 8.21, p = 0.002). Individuals who carried GPX1*TT and SOD2*CC genotypes had also an increased risk of POAG development but without significance after Bonferroni multiple test correction (OR = 6.66, p = 0.005). The present study supports the hypothesis that in combination, GSTO1/GSTO2, modulate the risk of primary open angle glaucoma.
Investigation of some variations of superoxide dismutase gene family in Turkish sporadic amyotrophic lateral sclerosis patients
2021, Brain DisordersAmyotrophic Lateral Sclerosis (ALS) is a devastating neurodegenerative disease caused by the death of motor neurons in the late stage of life and there is currently no effective treatment. To date, there has been much research into the association of ALS and a wide range of genes, including superoxide dismutase (SOD) 1 gene mutations. The SOD family of enzymes (SOD1, 2 and 3) are enzymes which are critical to the most important antioxidant system, protecting cells against reactive oxygen species (ROS). In this study, Asp90Ala and Gly93Ala mutations for SOD1, Ala(-9)Val and Ile58Thr variations for SOD2 and Arg202Leu mutation for SOD3 were investigated in sporadic ALS (SALS) patients and controls. Genotyping of 124 SALS patients and 124 controls was performed with polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). In SOD1 one patient was homozygous for the previously reported Asp90Ala mutation while no patients, or controls, had the Gly93Ala mutation. Statistical analysis of the data revealed that there was no allelic association between the cases and healthy controls for Ala(-9)Val polymorphism (p=0.538) in SOD2. In addition, no Ile58Thr mutation was found in any subject. Interestingly, two SALS patients were heterozygous for the SOD3 mutation, Arg202Leu. To the best of our knowledge there are no studies into the role of SOD3 mutations in ALS. Thus, this is the first report of an association between SOD3 Arg202Leu mutation and SALS in two patients, suggesting that this mutation may play a role in the pathology of ALS.
Concentration/activity of superoxide dismutase isozymes and the pro-/antioxidative status, in context of type 2 diabetes and selected single nucleotide polymorphisms (genes: INS, SOD1, SOD2, SOD3) – Preliminary findings
2021, Biomedicine and PharmacotherapyThe alterations in concentration/activity of superoxide dismutase isozymes in the context of type 2 diabetes or obesity are well-described. Moreover, many hereditary factors, including single-nucleotide polymorphisms (SNPs) of genes for coding insulin, insulin receptors, or insulin receptor substrates (INS, INSR, IRS1, IRS2) or superoxide dismutase isozymes (SOD1, SOD2, SOD3), have been linked with the incidence of obesity and diabetes. However, the underlying changes in the plasma concentration/activity of superoxide dismutase isozymes and their potential connection with the said hereditary factors remain unexplored. Previously, we have observed that the plasma concentration/activity of superoxide dismutase isozymes differs in the context of obesity and/or rs2234694 (SOD1) and rs4880 (SOD2) and that the concentrations of SOD1, SOD2, SOD3 are correlated with each other. Intersexual variability of SOD1 concentration was detected regardless of obesity. In this study, the variability of concentration/activity of superoxide dismutase isozymes in plasma is considered in the context of type 2 diabetes and/or SNPs: rs2234694 (SOD1), rs5746105 (SOD2), rs4880 (SOD2), rs927450 (SOD2), rs8192287 (SOD3). Genotypic variability of SNP rs3842729 (INS), previously studied in the context of insulin-dependent diabetes, is investigated in terms of selected clinical parameters associated with type 2 diabetes. This study revealed higher SOD1 concentration in diabetic men compared to women, and extremely high SOD1 concentration, higher total superoxide dismutase, and copper-zinc superoxide dismutase activity, and lower superoxide dismutase and copper-zinc superoxide dismutase activity (when adjusted for the concentration of SODs) in the diabetic group regardless of sex. Multiple logistic regression, applied to explore possible links between the studied SNPs and other factors with the odds of type 2 diabetes or obesity, revealed that the genotypic variability of rs4880 (SOD2) could affect these odds, supporting the findings of several other studies.
Antioxidant vitamins and genetic polymorphisms in breast cancer
2021, Cancer: Oxidative Stress and Dietary AntioxidantsThe effects of dietary factors on cancer development were inconsistent partly due to the study designs including the characteristics of the study population and the potential inaccuracies of dietary assessment and also due to the relationship may be influenced by genetic factors. The studies on the genetic influence on the relationship between dietary factors and cancer development are also equivocal. The modification of a phenotype to the relationship of dietary factors on cancer development could influence the inconsistencies of results from cancer molecular epidemiologic studies. One example is the inconsistent effects of folic acid on the risk of breast cancer. The degradation of the enzyme’s (MTHFR) capacity to use substrate may be affected by genetic polymorphism (genotype 677TT), which determines reduced enzyme activity. Given the evidence that diet can modify cancer risk, gene-diet interactions in cancer etiology would be anticipated. However, much of the evidence in this area comes from observational epidemiology, which limits the causal inference. Thus, the investigation of these interactions is essential to gain a full understanding of the impact of genetic variation on health outcomes.
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