Molecular Hydrogen Enhances Proliferation of Cancer Cells That Exhibit Potent Mitochondrial Unfolded Protein Response.

Molecular hydrogen ameliorates pathological states in a variety of human diseases, animal models, and cell models, but the effects of hydrogen on cancer have been rarely reported. In addition, the molecular mechanisms underlying the effects of hydrogen remain mostly unelucidated. We found that hydrogen enhances proliferation of four out of seven human cancer cell lines (the responders). The proliferation-promoting effects were not correlated with basal levels of cellular reactive oxygen species. Expression profiling of the seven cells showed that the responders have higher gene expression of mitochondrial electron transport chain (ETC) molecules than the non-responders. In addition, the responders have higher mitochondrial mass, higher mitochondrial superoxide, higher mitochondrial membrane potential, and higher mitochondrial spare respiratory capacity than the non-responders. In the responders, hydrogen provoked mitochondrial unfolded protein response (mtUPR). Suppression of cell proliferation by rotenone, an inhibitor of mitochondrial ETC complex I, was rescued by hydrogen in the responders. Hydrogen triggers mtUPR and induces cell proliferation in cancer cells that have high basal and spare mitochondrial ETC activities.

Ginsenoside Rh2 stimulates the production of mitochondrial reactive oxygen species and induces apoptosis of cervical cancer cells by inhibiting mitochondrial electron transfer chain complex.

Ginsenoside Rh2 (G­Rh2) is a monomeric compound that extracted from ginseng and possesses anti­cancer activities both in vitro and in vivo. Previously, we reported that G­Rh2 induces apoptosis in HeLa cervical cancer cells and that the process was related to reactive oxygen species (ROS) accumulation and mitochondrial dysfunction. However, the upstream mechanisms of G­Rh2, along with its cellular targets, remain to be elucidated. In the present study, the Cell Counting Kit­8 assay, flow cytometry and Hoechst staining revealed that G­Rh2 significantly inhibited cell viability and induced apoptosis of cervical cancer cells. However, G­Rh2 was demonstrated to be non­toxic to End1/e6e7 cells. JC­1, rhodamine 123 staining, oxidative phosphorylation and glycolysis capacity assays demonstrated that G­Rh2 exposure caused an immediate decrease in mitochondrial transmembrane potential due to its inhibition of mitochondrial oxidative phosphorylation, as well as glycolysis, both of which reduced cellular ATP production. Western blotting and electron transport chain (ETC) activity assays revealed that G­Rh2 significantly inhibited the activity of ETC complexes I, III and V. Overexpression of ETC complex III partially significantly restored mitochondrial ROS and inhibited the apoptosis of cervical cancer cells induced by G­Rh2. The predicted results of binding energy in molecular docking, confirmed that G­Rh2 was highly likely to induce mitochondrial ROS production and promote cell apoptosis by targeting the ETC complex, especially for ETC complex III. Taken together, the present results revealed the potential anti­cervical cancer activity of G­Rh2 and provide direct evidence for the contribution of impaired ETC complex activity to cervical cancer cell death.

Can Alternative Metabolic Pathways and Shunts Overcome Salinity Induced Inhibition of Central Carbon Metabolism in Crops?

The annual cost of lost crop production from exposure to salinity has major impacts on food security in all parts of the world. Salinity stress disturbs energy metabolism and knowledge of the impacts on critical processes controlling plant energy production is key to successfully breeding salt tolerant crops. To date, little progress has been achieved using classic breeding approaches to develop salt tolerance. The hope of some salinity researchers is that through a better understanding of the metabolic responses and adaptation to salinity exposure, new breeding targets can be suggested to help develop salt tolerant crops. Plants sense and react to salinity through a complex system of sensors, receptor systems, transporters, signal transducers, and gene expression regulators in order to control the uptake of salts and to induce tolerant metabolism that jointly leads to changes in growth rate and biomass production. During this response, there must be a balance between supply of energy from mitochondria and chloroplasts and energy demands for water and ion transport, growth, and osmotic adjustment. The photosynthetic response to salinity has been thoroughly researched and generally we see a sharp drop in photosynthesis after exposure to salinity. However, less attention has been given to the effect of salt stress on plant mitochondrial respiration and the metabolic processes that influence respiratory rate. A further complication is the wide range of respiratory responses that have been observed in different plant species, which have included major and minor increases, decreases, and no change in respiratory rate after salt exposure. In this review, we begin by considering physiological and biochemical impacts of salinity on major crop plants. We then summarize and consider recent advances that have characterized changes in abundance of metabolites that are involved in respiratory pathways and their alternative routes and shunts in terms of energy metabolism in crop plants. We will consider the diverse molecular responses of cellular plant metabolism during salinity exposure and suggest how these metabolic responses might aid in salinity tolerance. Finally, we will consider how this commonality and diversity should influence how future research of the salinity responses of crops plants should proceed.

Renal Carcinogenesis, Tumor Heterogeneity, and Reactive Oxygen Species: Tactics Evolved.

SIGNIFICANCE: The number of kidney cancers is growing 3-5% each year due to unknown etiologies. Intra- and inter-tumor mediators increase oxidative stress and drive tumor heterogeneity. Recent Advances: Technology advancement in state-of-the-art instrumentation and methodologies allows researchers to detect and characterize global landscaping modifications in genes, proteins, and pathophysiology patterns at the single-cell level. CRITICAL ISSUES: We postulate that the sources of reactive oxygen species (ROS) and their activation within subcellular compartments will change over a timeline of tumor evolvement and contribute to tumor heterogeneity. Therefore, the complexity of intracellular changes within a tumor and ROS-induced tumor heterogeneity coupled to the advancement of detecting these events globally are limited at the level of data collection, organization, and interpretation using software algorithms and bioinformatics. FUTURE DIRECTIONS: Integrative and collaborative research, combining the power of numbers with careful experimental design, protocol development, and data interpretation, will translate cancer biology and therapeutics to a heightened level or leave the abundant raw data as stagnant and underutilized. Antioxid. Redox Signal. 25, 685-701.