Evaluation of Thiol Homeostasis in Multiple Sclerosis and Neuromyelitis Optica Spectrum Disorders

Objectives: The aim of this pilot study was to evaluate dynamic thiol-disulfide homeostasis as a novel oxidative stress parameter in multiple sclerosis (MS), neuromyelitis optica spectrum disorders (NMOSD), and myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) to better understand the role of thiol homeostasis in neuroimmunological diseases.Methods: A total of 85 participants were included in this study, consisting of 18 healthy controls, 52 patients diagnosed with MS, seven with NMOSD, and eight with MOGAD. We measured total thiol (–SH+-S–S–) and native thiol (–SH) levels in the serum of all the participants, and in a subset of patients (n = 11), these parameters were investigated in paired cerebrospinal fluid (CSF) and serum samples. Dynamic disulfide concentrations were calculated separately. Finally, we determined if there was any relationship between clinical features and dynamic thiol homeostasis.Results: There was a statistically significant difference between serum and CSF levels of biomarkers of thiol homeostasis. Serum total thiol (317.88 ± 66.04) and native thiol (211.61 ± 44.15) levels were significantly lower in relapsed patients compared to those in remission (368.84 ± 150.36 vs. 222.52 ± 70.59, respectively).Conclusions: Oxidative stress plays a crucial role in the physiopathology of neuroimmunological diseases. Thiol homeostasis may be useful for monitoring disease activity.

Is There A Relationship Between The Umbilical Cord Coiling Index And Oxidative Stress Markers And SGA Fetuses?

Objective: We aimed to investigate the relationship between umblical coiling index and thiol/disulfide balance in SGA newborns to compare with AGA newborns. Material and Methods: Fetal umbilical cord serum samples were collected during labour and the thiol/disulfide homeostasis was measured. After birth, umbilical cords were collected and cord parameters were examined including, length, number of coils, umbilical cord index. Results: Significant decrease in native thiol, total thiol, and a significant increase in disulfide, disulfide/native thiol ratio and disulfide/total thiol ratios were observed in the study group while native thiol/total thiol ratio levels of the two groups did not reach to a statistical significance. Conclusion: The results of this study showed that SGA babies had altered thiol homeostasis in favor of oxidative stress.

Nrf2 is activated by disruption of mitochondrial thiol homeostasis but not by enhanced mitochondrial superoxide production

The transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) regulates the expression of genes involved in antioxidant defenses to modulate fundamental cellular processes such as mitochondrial function and glutathione metabolism. Previous reports proposed that mitochondrial ROS production and disruption of the glutathione pool activate the Nrf2 pathway, suggesting that Nrf2 senses mitochondrial redox signals and/or oxidative damage and signals to the nucleus to respond appropriately. However, until now it has not been possible to disentangle the overlapping effects of mitochondrial superoxide/ hydrogen peroxide production as a redox signal from changes to mitochondrial thiol homeostasis on Nrf2. Recently, we developed mitochondria-targeted reagents that can independently induce mitochondrial superoxide and hydrogen peroxide production (MitoPQ), or selectively disrupt mitochondrial thiol homeostasis (MitoCDNB). Using these reagents, here we have determined how enhanced generation of mitochondrial superoxide and hydrogen peroxide, or disruption of mitochondrial thiol homeostasis affect activation of the Nrf2 system in cells, which was assessed by Nrf2 protein level, nuclear translocation and expression of its target genes. We found that selective disruption of the mitochondrial glutathione pool and inhibition of its thioredoxin system by MitoCDNB led to Nrf2 activation, while using MitoPQ to enhance production of mitochondrial superoxide and hydrogen peroxide alone did not. We further showed that Nrf2 activation by MitoCDNB requires cysteine sensors of Kelch-like ECH-associated protein 1 (Keap1). These findings provide important information on how disruption to mitochondrial redox homeostasis is sensed in the cytoplasm and signaled to the nucleus.

Dynamic disulfide/thiol homeostasis in lead exposure denoted by a novel method

Lead is a toxic heavy metal, and prevention of human exposure to lead has not been accomplished yet. The toxicity of lead is continually being investigated, and the molecular mechanisms of its toxicity are still being revealed. In this study, we used a novel method to examine thiol (SH)/disulfide homeostasis in workers who were occupationally exposed to lead. A total of 80 such workers and 70 control subjects were evaluated, and their native and total SH values were measured in serum using a novel method; their blood lead levels were also assessed. The novel method used for SH measurements was based on the principle of measuring native SH, after which disulfide bonds were reduced and total SHs were measured. These measurements allowed us to calculate disulfide amounts, disulfide/total SH percent ratios, disulfide/native SH percent ratios, and native SH /total SH percent ratios. We found that disulfide levels were significantly higher in workers who were exposed to lead (21.08(11.1–53.6) vs. 17.9(1.7–25), p < 0.001). Additionally, the disulfide/native SH and disulfide/total SH percent ratios were higher in exposed workers, while the native SH/total SH percent ratios were higher in the control subjects. Furthermore, the lead and disulfide levels showed a positive correlation, with p < 0.001 and a correlation coefficient of 0.378. Finally, the novel method used in this study successfully showed a switch from SH to disulfide after lead exposure, and the method is fully automated, easy, cheap, reliable, and reproducible. Use of this method in future cases may provide valuable insights into the management of lead exposure.