Non-alcoholic fatty liver disease (NAFLD) is a spectrum of metabolic abnormalities ranging from simple triglyceride accumulation in the hepatocytes to hepatic steatosis with inflammation, ballooning and fibrosis. It has been demonstrated that the pathogenesis of NAFLD involves increased oxidative stress, with consumption of the major cellular antioxidant, glutathione (GSH). Liver has a fundamental role in sulfur compound metabolism, although the data reported on plasma thiols status in NAFLD are conflicting. We recruited 63 NAFLD patients, and we analyzed all plasma thiols, such as homocysteine (Hcy), cysteine (Cys), cysteinylglycine (CysGly) and GSH, by high-performance liquid chromatography (HPLC) with fluorescence detection. Hcy, Cys and CysGly plasma levels increased in NAFLD patients (p < 0.0001); whereas GSH levels were decreased in NAFLD patients when compared to controls (p < 0.0001). On the contrary, patients with steatohepatitis exhibited lower levels of Hcy and Cys than subjects without. Furthermore, a positive correlation was found between Hcy and Cys and the presence of fibrosis in children with NAFLD. Taken together, these data demonstrated a defective hepatic sulfur metabolism in children with NAFLD, and that high levels of Hcy and Cys probably correlates with a pattern of more severe histological liver damage, due to mechanisms that require further studies.

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These findings show a relevant in vivo disturbance of glutathione metabolism underlining the contribution of glutathione pool depletion to the redox imbalance in treated cblC patients. Our study may be helpful in addressing future research to better understanding the pathogenetic mechanism of the disease and in developing new therapeutic approaches, including the use of novel vitamin B₁₂ derivatives.

Hyperhomocysteinemia (hHcy) is a risk\ud factor in the progression of chronic kidney disease (CKD).\ud In type 2 diabetes (T2D), hHcy is strongly associated with\ud increased risk of cardiovascular disease. Vitamin B12 and\ud folic acid supplementation have been reported to lower\ud homocysteine (tHcy) levels, but no data on plasma tHcy,\ud cysteine (Cys), folate and vitamin B12 levels in T2D-CKD\ud patients are reported.\ud Procedures tHcy and Cys levels were analyzed in 178\ud T2D-CKD patients by high performance liquid chromatography\ud (HPLC) with fluorescence detection. In addition,\ud we determined folate and vitamin B12 levels using a\ud chemiluminescence method.\ud Results tHcy and Cys levels were increased in T2D\ud patients, and this rise positively correlated with the CKD\ud stage (P\0.001). Folate levels were comparable to controls\ud at various CKD stages, whereas vitamin B12 levels\ud were lower, except at stage IV. We did not find any\ud correlation between B-vitamins and levels of tHcy and Cys,\ud regardless of the CKD stage.\ud Conclusions This is the first study reporting tHcy, Cys\ud and B-vitamins status in T2D-CKD patients. Although\ud limited to our cohort of 178 patients, our findings could be\ud helpful in clarifying the conflicting literature regarding\ud B-vitamins supplementation. Further studies are necessary\ud before any Hcy-lowering therapy can be safely established\ud in T2D-CKD subjects

Methylmalonic acidemia with homocystinuria, cobalamin deficiency type C (cblC) (MMACHC) is the most common inborn error of cobalamin metabolism. Despite a multidrug treatment, the long-term follow-up of early-onset patients is often unsatisfactory, with progression of neurological and ocular impairment. Here, the in-vivo proteome of control and MMACHC lymphocytes (obtained from patients under standard treatment with OHCbl, betaine, folate and L-carnitine) was quantitatively examined by two dimensional differential in-gel electrophoresis (2D-DIGE) and mass spectrometry. Twenty three proteins were found up-regulated and 38 proteins were down-regulated. Consistent with in vivo studies showing disturbance of glutathione metabolism, a deregulation in proteins involved in cellular detoxification, especially in glutathione metabolism was found. In addition, relevant changes were observed in the expression levels of proteins involved in intracellular trafficking and protein folding, energy metabolism, cytoskeleton organization and assembly. This study demonstrates relevant changes in the proteome profile of circulating lymphocytes isolated from treated cblC patients. Some results confirm previous observations in vivo on fibroblast, thus concluding that some dysregulation is ubiquitous. On the other hand, new findings could be tissue-specific. These observations expand our current understanding of the cblC disease and may ignite new research and therapeutic strategies to treat this disorder.