Sten Orrenius, M.D., Ph.D., pioneered many areas of cellular and molecular toxicology and made seminal contributions to our knowledge of oxidative stress and glutathione (GSH) metabolism, organellar functions and Ca+2-dependent mechanisms of cell death, and mechanisms of apoptosis. On the occasion of his 80th birthday, we summarize current knowledge on redox biology of manganese (Mn) and its role in mechanisms of cell death. Mn is found in all organisms and has critical roles in cell survival and death mechanisms by regulating Mn-containing enzymes such as manganese superoxide dismutase (SOD2) or affecting expression and activity of caspases. Occupational exposures to Mn cause “manganism”, a Parkinson's disease-like condition of neurotoxicity, and experimental studies show that Mn exposure leads to accumulation of Mn in the brain, especially in mitochondria, and neuronal cell death occurs with features of an apoptotic mechanism. Interesting questions are why a ubiquitous metal that is essential for mitochondrial function would accumulate to excessive levels, cause increased H2O2 production and lead to cell death. Is this due to the interactions of Mn with other essential metals, such as iron, or with toxic metals, such as cadmium? Why is the Mn loading in the human brain so variable, and why is there such a narrow window between dietary adequacy and toxicity? Are non-neuronal tissues similarly vulnerable to insufficiency and excess, yet not characterized? We conclude that Mn is an important component of the redox interface between an organism and its environment and warrants detailed studies to understand the role of Mn as a mitochondrial life-death switch.

BACKGROUND.Bone is among the most common sites of metastasis in patients with advanced cancer, and the development of bone metastases places patients at increased risk for skeletal complications.METHODS.This retrospective claims analysis included only patients with a diagnosis of bone metastasis who had a single type of solid tumor of the breast (women), prostate, or lung and experienced ≥1 skeletal complication between January 2002 and October 2005.RESULTS.The mean follow‐up (±standard deviation) for zoledronic acid (ZA)‐treated patients versus untreated patients was 12.2 ± 9.05 months versus 8.7 ± 9.28 months, respectively (P < .001). The monthly rate of skeletal complications in ZA‐treated patients versus untreated patients was 0.29 ± 0.3 per month versus 0.43 ± 0.4 per month, respectively (P < .001). Persistent ZA use was associated with longer follow‐up duration (P < .05) and a greater probability of continuing follow‐up. Greater persistency was associated with lower monthly rates of skeletal complications (P < .05). The length of follow‐up for ZA use according to the recommended dosing schedule was 17.11 months compared with 9.93 months for nonrecommended schedules and 8.68 months for no treatment (analysis of variance; P < .001). The rate of skeletal complications with ZA use on the recommended schedule was 0.16 events per month versus 0.31 events per month for nonrecommended schedules and 0.43 events per month for no treatment. In the subgroup analysis, the mean time to first complication was 185 ± 210 days in the ZA‐treated group versus 98 ± 161 days in the untreated group (P < .0001). The mean time from the first complication to the second complication was 111 ± 124 days in the ZA‐treated group versus 86 ± 114 days in the untreated group (P < .05).CONCLUSIONS.Real‐world evidence indicated that ZA reduced the skeletal morbidity rate and delayed the time to skeletal complications. Cancer 2008. © 2008 American Cancer Society.

No abstract

Mitochondria possess reserve bioenergetic capacity, supporting protection and resilience in the face of disease. Approaches are limited to understand factors that impact mitochondrial functional reserve in humans. We applied the mitochondrial stress test (MST) to platelets from healthy subjects and found correlations between energetic parameters and mitochondrial function. These parameters were not correlated with mitochondrial complex I-IV activities, however, suggesting that other factors affect mitochondrial bioenergetics and metabolism. Platelets from African American patients with sickle cell disease also differed from controls, further showing that other factors impact mitochondrial bioenergetics and metabolism. To test for correlations of platelet metabolites with energetic parameters, we performed an integrated analysis of metabolomics and MST parameters. Subsets of metabolites, including fatty acids and xenobiotics correlated with mitochondrial parameters. The results establish platelets as a platform to integrate bioenergetics and metabolism for analysis of mitochondrial function in precision medicine.

Almost invariably, humans become ill during primary infections with malaria parasites which is a pathology associated with oxidative stress and perturbations in metabolism. Importantly, repetitive exposure to Plasmodium results in asymptomatic infections, which is a condition defined as clinical tolerance. Integration of transcriptomics and metabolomics data provides a powerful way to investigate complex disease processes involving oxidative stress, energy metabolism and immune cell activation. We used metabolomics and transcriptomics to investigate the different clinical outcomes in a P. vivax controlled human malaria infection trial. At baseline, the naïve and semi-immune subjects differed in the expression of interferon related genes, neutrophil and B cell signatures that progressed with distinct kinetics after infection. Metabolomics data indicated differences in amino acid pathways and lipid metabolism between the two groups. Top pathways during the course of infection included methionine and cysteine metabolism, fatty acid metabolism and urea cycle. There is also evidence for the activation of lipoxygenase, cyclooxygenase and non-specific lipid peroxidation products in the semi-immune group. The integration of transcriptomics and metabolomics revealed concerted molecular events triggered by the infection, notably involving platelet activation, innate immunity and T cell signaling. Additional experiment confirmed that the metabolites associated with platelet activation genes were indeed enriched in the platelet metabolome.