Determination of Cytokines and Oxidative Stress Biomarkers in Cognitive Impairment Induced by Methylmalonic Acidemia

Abstract

<b><i>Objective:</i></b> Methylmalonic acidemia (MMA) is the most common organic acidemia in children. Many patients with MMA suffered from cognitive impairments. The aim of this study was to identify the significance of cytokines and oxidative stress biomarkers in MMA-induced cognitive impairment. <b><i>Methods:</i></b> We enrolled 64 children with combined MMA and homocystinuria and 64 age- and sex-matched healthy volunteers. Participants were subsequently classified as with or without cognitive impairments using a uniform neuropsychological assessment test. Serum samples were collected. The serum levels of cytokines and oxidative stress biomarkers were measured using the ELISA or chemical methods. <b><i>Results:</i></b> Compared to control group, the serum levels of tumor necrosis factor (TNF)-α, interleukin (IL)-6, malondialdehyde (MDA), and nitric oxide (NO) in the MMA patients increased markedly (<i>p</i> < 0.05); glutathione (GSH) and superoxide dismutase (SOD) decreased obviously (<i>p</i> < 0.01). The levels of IL-6, TNF-α, NO, and MDA in the serum were negatively associated with DQ or IQ scores. The levels of GSH and SOD in the serum were positively correlated with DQ or IQ scores. After receiver operating characteristic curve analysis, NO was the most useful individual marker for distinguishing the cognitive dysfunction, corresponding to the area under ROC curve (AUC) of 0.82 (95% CI, 0.74–0.91), sensitivity of 76.60%, and specificity of 80.25%. GSH and MDA were also useful for diagnosis of MMA-induced cognitive dysfunction, corresponding to the AUC of 0.80 (95% CI, 0.70–0.89), and 0.73 (95% CI, 0.63–0.82), respectively. The sensitivity and specificity of GSH were 72.34 and 80.25%, respectively. The sensitivity and specificity of MDA were 85.11 and 51.85%, respectively. <b><i>Conclusions:</i></b> The high-concentration methylmalonic acid in the blood induced immune cells to release pro-inflammatory cytokines such as TNF-α and IL-6. These cytokines and high-concentration methylmalonic acid stimulated the immune cells to produce reactive oxygen species (ROS) and reactive nitrogen species (RNS). The serum methylmalonic acid, cytokines, ROS, and RNS were across the blood-brain barrier and induced cognitive impairment. The small molecule substances such as serum NO, MDA, and GSH participated in the process of neuroinflammation and oxidative stress injury induced by MMA and could be useful for distinguishing the cognitive impairment.

Tumor-produced and aging-associated oncometabolite methylmalonic acid promotes cancer-associated fibroblast activation to drive metastatic progression

“…The role of circulatory IL-6 in metastasis and therapy resistance has been previously observed, and is long known to be increased in the serum with age 29,30 . IL-6 was also recently reported to be increased in the serum of methylmalonic acidemia patients 31 . The discovery of a specific mode of IL-6 delivery from stroma to tumor through EVs, however, likely confers a particularly calibrated and potent effect.…”

Renal outcome and plasma methylmalonic acid levels after isolated or combined liver or kidney transplantation in patients with methylmalonic acidemia: A multicenter analysis

“…This difference is most likely due to a lower enzymatic activity provided by the kidney transplant; lower kidney function after isolated kidney transplantation might also contribute to higher plasma MMA levels. Metabolic impairment associated with high MMA plasma levels has been repeatedly reported [32][33][34]; these data should be considered for the definition of a transplant strategy in MMA patients.…”

Tumor-produced aging-associated oncometabolite, methylmalonic acid, promotes cancer-associated fibroblast activation to drive metastatic progression

“…The role of circulatory IL-6 in metastasis and therapy resistance has been previously observed, and is long known to be increased in the serum with age (27,28). IL-6 was also reported to be increased in the serum of Methylmalonic acidemia patients recently (29).The discovery of a speci c mode of IL-6 delivery from TME to stroma through extracellular vesicles, however, likely confers a particularly calibrated and potent effect. The proportion of IL-6 released freely or delivered through EVs has been shown to vary widely and depend on the biological systems involved; for example, almost all IL-6 released from monocytes are free, while all IL-6 released from T cells are encapsulated (30).…”