Our previous study indicated that intravenous vitamin C (IVC) treatment concurrent with modulated electrohyperthermia (mEHT) was safe and improved the quality of life (QoL) of non-small-cell lung cancer (NSCLC) patients. The aim of this trial was to further verify the efficacy of the above combination therapy in previously treated patients with refractory advanced (stage IIIb or IV) NSCLC. A total of 97 patients were randomized to receive IVC and mEHT plus best supportive care (BSC) (n = 49 in the active arm, receiving 1 g/kg * d IVC concurrently with mEHT, three times a week for 25 treatments in total) or BSC alone (n = 48 in the control arm). After a median follow-up of 24 months, progression-free survival (PFS) and overall survival (OS) were significantly prolonged by combination therapy compared to BSC alone (PFS: 3 months vs 1.85 months, P < 0.05; OS: 9.4 months vs 5.6 months, P < 0.05). QoL was significantly increased in the active arm despite the advanced stage of disease. The 3-month disease control rate after treatment was 42.9% in the active arm and 16.7% in the control arm (P < 0.05). Overall, IVC and mEHT may have the ability to improve the prognosis of patients with advanced NSCLC.

Fluoride intoxication generates free radicals, causing oxidative stress that plays a critical role in the progression of nephropathy. In the present study, we hypothesized that epigallocatechin gallate (EGCG), found in green tea, protects the kidneys of rats treated with fluoride by preventing oxidative stress, inflammation, and apoptosis. Pretreatment of fluoride-treated rats with EGCG resulted in a significant normalization of creatinine clearance and levels of urea, uric acid, and creatinine. Fluoride intoxication significantly increased renal oxidative stress markers and decreased the levels of renal enzymatic and non-enzymatic antioxidants. In addition, renal NO, TNF-α, IL-6 and NF-κB were also increased in the renal tissue of fluoride-treated rats. Further, EGCG pretreatment produced a significant improvement in renal antioxidant status and reduced lipid peroxidation, protein carbonylation and the levels of inflammatory markers in fluoride-treated kidney. Similarly, mRNA and protein analyses showed that EGCG pretreatment normalized the renal expression of Nrf2/Keap1 and its downstream regulatory proteins in fluoride-treated rat kidney. EGCG also effectively attenuated fluoride-induced renal apoptosis by the up-regulation of anti-apoptotic proteins such as Bcl-2 and down-regulation of Bax, caspase-3, caspase-9 and cytochrome c. Histology and immunohistochemical observations of Kim-1 provided further evidence that EGCG effectively protects the kidney from fluoride-mediated oxidative damage. These results suggest that EGCG ameliorates fluoride-induced oxidative renal injury by activation of the Nrf2/HO-1 pathway.

Activation of the transcription factor Nrf2 (nuclear factor-erythroid 2-related factor 2) is one of the major cellular defense lines against oxidative and xenobiotic stress, but also influences genes involved in lipid and glucose metabolism. It is unresolved whether the cytoprotective and metabolic responses mediated by Nrf2 are connected or separable events in non-malignant cells. In this study we show that activation of Nrf2, either by the small molecule sulforaphane or knockout of the Nrf2 inhibitor Keap1, leads to increased cellular glucose uptake and increased glucose addiction in fibroblasts. Upon Nrf2 activation glucose is preferentially metabolized through the pentose phosphate pathway with increased production of NADPH. Interference with the supply of glucose or the pentose phosphate pathway and NADPH generation not only hampers Nrf2-mediated detoxification of reactive oxygen species on the enzyme level but also Nrf2-initiated expression of antioxidant defense proteins, such as glutathione reductase and heme-oxygenase1. We conclude that the Nrf2-dependent protection against oxidative stress relies on an intact pentose phosphate pathway and that there is crosstalk between metabolism and detoxification already at the level of gene expression in mammalian cells.