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Elevated iron deposition has been reported in Parkinson's disease (PD). However, the route of iron uptake leading to high deposition in the substantia nigra is unresolved. Here, we show a mechanism in enhanced Fe2+ 1 uptake via S-nitrosylation of divalent metal transporter 1 (DMT1). While DMT1 could be S-nitrosylated by exogenous nitric oxide donors, in human PD brains, endogenously S-nitrosylated DMT1 was detected in postmortem substantia nigra. Patch-damp electrophysiological recordings and iron uptake assays confirmed increased Mn2+ or Fe2+ uptake through S-nitrosylated DMT1. We identified two major S-nitrosylation sites, C23 and C540, by mass spectrometry, and DMT1 C23A or C540A substitutions abolished nitric oxide (NO)- mediated DMT1 current increase. To evaluate in vivo significance, lipopolysaccharide (LPS) was stereotaxically injected into the substantia nigra of female and male mice to induce inflammation and production of NO. The intranigral LPS injection resulted in corresponding increase in Fe2+ deposition, JNK activation, dopaminergic neuronal loss and deficit in motoric activity, and these were rescued by the NO synthase inhibitor l-NAME or by the DMTl-selective blocker ebselen. Lentiviral knockdown of DMT1 abolished LPS-induced dopaminergic neuron loss. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer death worldwide, with region specific etiologies. Despite improvements made in the diagnosis of HCC, the prognosis of HCC patients remains poor due to the high recurrence rate of HCC. There is an urgent need for development of prognostic biomarkers to predict the risk of recurrence in HCC patients after "curative" treatment. Such stratification may aid in patient management and development of personalized medicine for HCC treatment. Omics based studies facilitate the study of global changes in biomolecules in a disease in a high throughput manner, and hence are well poised to understand the complex changes which led to HCC recurrence. The quantitative nature of data obtained from omics based studies allow for development of prognostic biomarkers based on changes in gene, protein and metabolite expression. In this review, we surveyed the application of transcriptomics, proteomics and metabolomics in the study of HCC recurrence. We summarised the data in the literature from these three fields of studies that claimed to be prognostic for HCC recurrence. We critiqued on the limitations of each area of research and the challenges faced in translating the research results for clinical application in predicting HCC recurrence.