A Blood Biomarker for Duchenne Muscular Dystrophy Shows That Oxidation State of Albumin Correlates with Protein Oxidation and Damage in Mdx Muscle

Al-Mshhdani, Basma A.; Grounds, Miranda D.; Arthur, Peter G.; Terrill, Jessica R.

doi:10.3390/antiox10081241

“…The in vivo antioxidant role of Cys34 is confirmed, although indirectly, by several studies reporting a relationship between the Cys34 reduction/cysteinylation increase and the severity of chronic diseases for which oxidative stress is a significant etiological manifestation, including chronic liver disease, kidney diseases, diabetes mellitus [ 30 ], muscle dystropathology [ 31 ], and heart failure [ 5 ]. Moreover, the adducts of Cys34 with electrophilic reaction products have been reported to increase in ischemia-reperfusion injury during hepatectomy [ 32 ] and in colorectal cancer patients [ 33 ].…”

Section: Discussionmentioning

confidence: 99%

N-Acetylcysteine Regenerates In Vivo Mercaptoalbumin

Altomare

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Brioschi

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Eligini

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et al. 2022

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Human serum albumin (HSA) represents the most abundant plasma protein, with relevant antioxidant activity due to the presence of the sulfhydryl group on cysteine at position 34 (Cys34), the latter being one of the major target sites for redox-dependent modifications leading to the formation of mixed disulfide linkages with low molecular weight thiols. Thiolated forms of HSA (Thio-HSA) may be useful as markers of an unbalanced redox state and as a potential therapeutic target. Indeed, we have previously reported that albumin Cys34 can be regenerated in vitro by N-Acetylcysteine (NAC) through a thiol-disulfide breaking mechanism, with a full recovery of the HSA antioxidant and antiplatelet activities. With this case study, we aimed to assess the ability of NAC to regenerate native mercaptoalbumin (HSA-SH) and the plasma antioxidant capacity in subjects with redox unbalance, after oral and intravenous administration. A placebo-controlled crossover study, single-blinded, was performed on six hypertensive subjects, randomized into two groups, on a one-to-one basis with NAC (600 mg/die) or a placebo, orally and intravenously administered. Albumin isoforms, HSA-SH, Thio-HSA, and glutathione levels were evaluated by means of mass spectrometry. The plasma antioxidant activity was assessed by a fluorimetric assay. NAC, orally administered, significantly decreased the Thio-HSA levels in comparison with the pre-treatment conditions (T0), reaching the maximal effect after 60 min (−24.7 ± 8%). The Thio-HSA reduction was accompanied by a concomitant increase in the native HSA-SH levels (+6.4 ± 2%). After intravenous administration of NAC, a significant decrease of the Thio-HSA with respect to the pre-treatment conditions (T0) was observed, with a maximal effect after 30 min (−68.9 ± 10.6%) and remaining significant even after 6 h. Conversely, no effect on the albumin isoforms was detected with either the orally or the intravenously administered placebo treatments. Furthermore, the total antioxidant activity of the plasma significantly increased after NAC infusion with respect to the placebo (p = 0.0089). Interestingly, we did not observe any difference in terms of total glutathione corrected for hemoglobin, ruling out any effect of NAC on the intracellular glutathione and supporting its role as a disulfide-breaking agent. This case study confirms the in vitro experiments and demonstrates for the first time that NAC is able to regenerate mercaptoalbumin in vivo, allowing us to hypothesize that the recovery of Cys34 content can modulate in vivo oxidative stress and, hopefully, have an effect in oxidative-based diseases.

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“…Our Special Issue presents innovative research [ 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 ] and review [ 13 , 14 , 15 ] papers addressing many of these questions related to the fundamental OS involvement in the onset and progression of several acute and chronic diseases, and about the correlated biomarkers and potential therapies. Precisely, the 12 research articles [ 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 ] included in this Special Issue are focused on evidencing the OS role in diagnostics, signatures of the disease course, molecules involved, OS potential treatments and effects, and short- and long-term consequences.…”

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confidence: 99%

“…Our Special Issue presents innovative research [ 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 ] and review [ 13 , 14 , 15 ] papers addressing many of these questions related to the fundamental OS involvement in the onset and progression of several acute and chronic diseases, and about the correlated biomarkers and potential therapies. Precisely, the 12 research articles [ 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 ] included in this Special Issue are focused on evidencing the OS role in diagnostics, signatures of the disease course, molecules involved, OS potential treatments and effects, and short- and long-term consequences. Precisely, Chen et al [ 1 ], by performing a nano-electrospray ionization–mass spectrometry (nanoESI-MS)-based lipidomic profiling study on lipid accumulation and oxidation in kidney cells in the chronic kidney disease (CKD) model, confirmed the key role of OS and lipid dysregulation in renal lipid droplet (LD) alteration at the molecular level.…”

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confidence: 99%

“…Of note are, also, the results of two research articles [ 10 , 12 ], which demonstrated the key role of OS in non-alcoholic steatohepatitis (NASH), Duchenne muscular dystrophy (DMD) and their complications. Precisely, Hui et al [ 10 ], in the NASH model mice and by conducting a comprehensive lipidomic analysis covering both intact lipids and lipid hydroperoxides in the liver and kidney tissues using liquid chromatography–mass spectrometry (LC/MS), demonstrated that OS played a crucial role in lipid dysregulation and peroxidation at the molecular level.…”

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confidence: 99%

“…Thus, their data provided a better understanding of OS in NASH development from the view of lipid metabolism, providing direct evidence for the oxidative damage-caused lipid hydro-peroxidation in NASH. Terrill et al [ 12 ] elegantly documented by using the mdx mouse model of DMD that plasma Cys34 albumin thiol oxidation is a useful blood biomarker of OS in mdx mice, and changes in such thiol oxidation in plasma more closely reflect changes in protein thiol oxidation in dystrophic muscle, than the commonly used biomarker protein carbonylation. Thus, the data presented in this work suggest that albumin Cys34 thiol oxidation has the potential to be a useful robust blood biomarker of dystro-pathology and may be used to efficiently evaluate and advance the development of therapies for DMD.…”

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confidence: 99%

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