Reactive Oxygen Species: Beyond Their Reactive Behavior

Cellular homeostasis plays a critical role in how an organism will develop and age. Disruption of this fragile equilibrium is often associated with health degradation and ultimately, death. Reactive oxygen species (ROS) have been closely associated with health decline and neurological disorders, such as Alzheimer’s disease or Parkinson’s disease. ROS were first identified as by-products of the cellular activity, mainly mitochondrial respiration, and their high reactivity is linked to a disruption of macromolecules such as proteins, lipids and DNA. More recent research suggests more complex function of ROS, reaching far beyond the cellular dysfunction. ROS are active actors in most of the signaling cascades involved in cell development, proliferation and survival, constituting important second messengers. In the brain, their impact on neurons and astrocytes has been associated with synaptic plasticity and neuron survival. This review provides an overview of ROS function in cell signaling in the context of aging and degeneration in the brain and guarding the fragile balance between health and disease.

     

Reactive oxygen species-linked regulation of the multidrug resistance transporter P-glycoprotein in Nox-1 overexpressing prostate tumor spheroids

Expression of the multidrug resistance (MDR) transporter P-glycoprotein (P-gp) has been demonstrated to be regulated by hypoxia-inducible factor-1alpha (HIF-1alpha) and inhibited by intracellular reactive oxygen species (ROS). Herein, P-gp and HIF-1alpha expression were investigated in multicellular prostate tumor spheroids overexpressing the ROS-generating enzyme Nox-1 in comparison to the mother cell line DU-145. In Nox-1-overexpressing tumor spheroids (DU-145Nox1) generation of ROS as well as expression of Nox-1 was significantly increased as compared to DU-145 tumor spheroids. ROS generation was significantly inhibited in the presence of the NADPH-oxidase antagonists diphenylen-iodonium chloride (DPI) and 4-(2-aminoethyl)benzenesulfonyl fluoride (AEBSF). Albeit growth kinetic of DU-145Nox1 tumor spheroids was decreased as compared to DU-145 spheroids, elevated expression of Ki-67 was observed indicating increased cell cycle activity. In DU-145Nox1 tumor spheroids, expression of HIF-1alpha as well as P-gp was significantly decreased as compared to DU-145 spheroids, which resulted in an increased retention of the anticancer agent doxorubicin. Pretreatment with the free radical scavengers vitamin E and vitamin C increased the expression of P-gp as well as HIF-1alpha in Nox-1-overexpressing cells, whereas no effect of free radical scavengers was observed on mdr-1 mRNA expression. In summary, the data of the present study demonstrate that the development of P-gp-mediated MDR is abolished under conditions of elevated ROS levels, suggesting that the MDR phenotype can be circumvented by modest increase of intracellular ROS generation.     

Reactive electrophile species

The interest in reactive electrophile species (RES) stems largely from the fact that they can have powerful biological activities. RES stimulate the expression of cell survival genes as well many other genes commonly upregulated in environmental stress and pathogenesis. RES levels must be carefully controlled in healthy cells but their formation and destruction during stress is of great interest. Unlike many 'classical' signals and hormones, RES can potentially affect gene expression at all levels by chemically reacting with nucleic acids, proteins and small molecules as well as by indirectly lowering pools of cellular reductants. Recent works involving genetic approaches have begun to provide compelling evidence that, although excess RES production can lead to cell damage, lower levels of RES may modulate the expression of cell survival genes and may actually contribute to survival during severe stress.     

Reactive motility of dendrites

The neurohistological data on the nonspecific reactive phenomenon the dendrite neuroplasm excrescences were compared with intravital data on reactive mobility of the processes of the surviving neurons and nerve cells in tissue cultures. It was demonstrated that static pictures on histological preparations correspond to the stages of reactive reconstruction of live dendrites, such as retraction, extrusion and autotomy. The neuroplasmic excrescences reflect the reverse displacement of the neuroplasm associated with the process retraction rather than enhancement of its proximodistal flow.     

Reactive hyperemia in Raynaud's disease

We studied reactive hyperemia after ischemia, after cold, and after cold plus ischemia, in normal subjects, in fingers with Raynaud's phenomenon, and in fingers without Raynaud's phenomenon in hands where other fingers were affected by Raynaud's phenomenon. The results obtained demonstrate the existence of a criohyperdysestesia both in fingers with Raynaud's phenomenon and in fingers without Raynaud's phenomenon in hands where other fingers are affected by it.     

Reactive erosive arthritis in chimpanzees

Diagnosis of diseases of bone, without benefit of soft tissue, in vivo observation, or blood component analysis requires the development of new criteria for diagnosis. Analyzing chimpanzee skeletal populations, applying such criteria (e.g., lesion character, distribution, radiologic appearance, and sex ratios), revealed a picture indistinguishable from human spondyloarthropathy. As Africa has been shown to manifest this condition in indigenous human, chimpanzee, and lowland gorilla populations, the possibility of a non-species specific etiology is suggested.     

Reactive oxygen species in cancer

Abstract

Elevated rates of reactive oxygen species (ROS) have been detected in almost all cancers, where they promote many aspects of tumour development and progression. However, tumour cells also express increased levels of antioxidant proteins to detoxify from ROS, suggesting that a delicate balance of intracellular ROS levels is required for cancer cell function. Further, the radical generated, the location of its generation, as well as the local concentration is important for the cellular functions of ROS in cancer. A challenge for novel therapeutic strategies will be the fine tuning of intracellular ROS signalling to effectively deprive cells from ROS-induced tumour promoting events, towards tipping the balance to ROS-induced apoptotic signalling. Alternatively, therapeutic antioxidants may prevent early events in tumour development, where ROS are important. However, to effectively target cancer cells specific ROS-sensing signalling pathways that mediate the diverse stress-regulated cellular functions need to be identified. This review discusses the generation of ROS within tumour cells, their detoxification, their cellular effects, as well as the major signalling cascades they utilize, but also provides an outlook on their modulation in therapeutics.     

Reactive strategies in indirect reciprocity

Evolution of reactive strategy of indirect reciprocity is discussed, where individuals interact with others through the one-shot Prisoner's Dilemma game, changing their partners in every round. We investigate all of the reactive strategies that are stochastic, including deterministic ones as special cases. First we study adaptive dynamics of reactive strategies by assuming monomorphic population. Results are very similar to the corresponding evolutionary dynamics of direct reciprocity. The discriminating strategy, which prescribes cooperation only with those who cooperated in the previous round, cannot be an outcome of the evolution. Next we examine the case where the population includes a diversity of strategies. We find that only the mean 'discriminatoriness' in the population is the parameter that affects the evolutionary dynamics. The discriminating strategy works as a promoter of cooperation there. However, it is again not the end point of the evolution. This is because retaliatory defection, which was prescribed by the discriminating strategy, is regarded as another defection toward the society. These results caution that we have to reconsider the role of retaliatory defection much more carefully.