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Charcot first described amyotrophic lateral sclerosis (ALS) between 1865 and 1874 as a sporadic adult disease resulting from the idiopathic progressive degeneration of the motor neuronal system, resulting in rapid, progressive, and generalized muscle weakness and atrophy. There is no cure for ALS and no proven therapy to prevent it or reverse its course. There are two drugs specifically approved for the treatment of ALS, riluzol and edaravone, and many others have already been tested or are following clinical trials. However, at the present moment, we still cannot glimpse a true breakthrough in the treatment of this devastating disease. Nevertheless, our understanding of the pathophysiology of ALS is constantly growing. Based on this background, we know that oxidative stress, alterations in the NAD+-dependent metabolism and redox status, and abnormal mitochondrial dynamics and function in the motor neurons are at the core of the problem. Thus, different antioxidant molecules or NAD+ generators have been proposed for the therapy of ALS. This review analyzes these options not only in light of their use as individual molecules, but with special emphasis on their potential association, and even as part of broader combined multi-therapies. [ABSTRACT FROM AUTHOR]

Clinical applications of glucocorticoids (GC) in Oncology are dependent on their pro-apoptotic action to treat lymphoproliferative cancers, and to alleviate side effects induced by chemotherapy and/or radiotherapy. However, the mechanism(s) by which GC may also promote tumor progression remains unclear. GC receptor (GR) knockdown decreases the antioxidant protection of highly metastatic B16-F10 melanoma cells. We hypothesize that a GR antagonist (RU486, mifepristone) could increase the efficacy of BRAF-related therapy in BRAF V600E -mutated metastatic melanoma. In vivo formed spontaneous skin tumors were reinoculated into nude mice to expand the metastases of different human BRAF V600E melanoma cells. The GR content of melanoma cell lines was measured by [ 3 H]-labeled ligand binding assay. Nuclear Nrf2 and its transcription activity was investigated by RT-PCR, western blotting, and by measuring Nrf2- and redox state-related enzyme activities and metabolites. GR knockdown was achieved using lentivirus, and GR overexpression by transfection with the NR3C1 plasmid. shRNA-induced selective Bcl-xL, Mcl-1, AKT1 or NF-κB/p65 depletion was used to test the efficacy of vemurafenib (VMF) and RU486 against BRAF V600E -mutated metastatic melanoma. During early progression of skin melanoma metastases, RU486 and VMF induced a drastic metastases regression. However, treatment at an advanced stage of growth demonstrated the development of resistance to RU486 and VMF. This resistance was mechanistically linked to overexpression of specific proteins of the Bcl-2 family (Bcl-xL and Mcl-1 in our experimental models). We found that melanoma resistance is decreased if AKT and NF-κB signaling pathways are blocked. Our results highlight mechanisms by which metastatic melanoma cells adapt to survive., Competing Interests: None., (AJCR Copyright © 2019.)