NADPH oxidase (Nox) has a dedicated function of generating reactive oxygen species (ROS). Accumulating evidence suggests that Nox has an important role in signal transduction in cellular stress responses. We have reviewed the current evidence showing that the Nox system can be activated by a collection of chemical, physical, and biological cellular stresses. In many circumstances, Nox activation fits to the cellular stress response paradigm, in that (1) the response can be initiated by various forms of cellular stresses; (2) Nox-derived ROS may activate mitogen-activated protein kinases (extracellular signal-regulated kinase, p38) and c-Jun NH₂-terminal kinase, which are the core of the cell stress-response signaling network; and (3) Nox is involved in the development of stress cross-tolerance. Activation of the cell survival pathway by Nox may promote cell adaptation to stresses, whereas Nox may also convey signals toward apoptosis in irreversibly injured cells. At later stage after injury, Nox is involved in tissue repair by modulating cell proliferation, angiogenesis, and fibrosis. We suggest that Nox may have an integral role in cell stress responses and the subsequent tissue repair process. Understanding Nox-mediated redox signaling mechanisms may be of prominent significance at the crossroads of directing cellular responses to stress, aiming at either enhancing the stress resistance (in such situations as preventing ischemia-reperfusion injuries and accelerating wound healing) or sensitizing the stress-induced cytotoxicity for proliferative diseases such as cancer. Therefore, an optimal outcome of interventions on Nox will only be achieved when this is dealt with in a timely and disease-and stage-specific manner.

Uncontrolled fibrosis in organs like heart, kidney, liver and lung is detrimental and may lead to end-stage organ failure. Currently there is no effective treatment for fibrotic disorders. Transforming growth factor (TGF)-β has a fundamental role in orchestrating the process of fibrogenesis; however, interventions directly targeting TGF-β would have undesired systemic side effects due to the multiple physiological functions of TGF-β. Further characterization of the downstream signaling pathway(s) involved in TGF-β-mediated fibrosis may lead to discovery of novel treatment strategies for fibrotic disorders. Accumulating evidence suggests that Nox4 NADPH oxidase may be an important downstream effector in mediating TGF-β-induced fibrosis, while NADPH oxidase-dependent redox signaling may in turn regulate TGF-β/Smad signaling in a feed-forward manner. It is proposed that pharmacological inhibition of the Nox4 function may represent a novel approach in treatment of fibrotic disorders.

Disturbed cell autophagy is found in various cardiovascular disease conditions. Biomechanical stimuli induced by laminar blood flow have important protective actions against the development of various vascular diseases. However, the impacts and underlying mechanisms of shear stress on the autophagic process in vascular endothelial cells (ECs) are not entirely understood. Here we investigated the impacts of shear stress on autophagy in human vascular ECs. We found that shear stress induced by laminar flow, but not that by oscillatory or low-magnitude flow, promoted autophagy. Time-course analysis and flow cessation experiments confirmed that this effect was not a transient adaptive stress response but appeared to be a sustained physiological action. Flow had no effect on the mammalian target of rapamycin-ULK pathway, whereas it significantly upregulated Sirt1 expression. Inhibition of Sirt1 blunted shear stress-induced autophagy. Overexpression of wild-type Sirt1, but not the deacetylase-dead mutant, was sufficient to induce autophagy in ECs. Using both of gain- and loss-of-function experiments, we showed that Sirt1-dependent activation of FoxO1 was critical in mediating shear stress-induced autophagy. Shear stress also induced deacetylation of Atg5 and Atg7. Moreover, shear stress-induced Sirt1 expression and autophagy were redox dependent, whereas Sirt1 might act as a redox-sensitive transducer mediating reactive oxygen species-elicited autophagy. Functionally, we demonstrated that flow-conditioned cells are more resistant to oxidant-induced cell injury, and this cytoprotective effect was abolished after inhibition of autophagy. In summary, these results suggest that Sirt1-mediated autophagy in ECs may be a novel mechanism by which laminar flow produces its vascular-protective actions.

In this review, we summarize advances in our understanding of redox-sensitive mechanisms that regulate adipogenesis. Current evidence indicates that reactive oxygen species may act to promote both the initiation of adipocyte lineage commitment of precursor or stem cells, and the terminal differentiation of preadipocytes to mature adipose cells. These can involve redox regulation of pathways mediated by receptor tyrosine kinases, peroxisome proliferator-activated receptor γ (PPARγ), PPARγ coactivator 1α (PGC-1α), AMP-activated protein kinase (AMPK), and CCAAT/enhancer binding protein β (C/EBPβ). However, the precise roles of ROS in adipogenesis in vivo remain controversial. More studies are needed to delineate the roles of reactive oxygen species and redox signaling mechanisms, which could be either positive or negative, in the pathogenesis of obesity and related metabolic disorders.

Background: Biological markers that can be used to predict the risk of intracranial aneurysms ( IA s) are not available. Methods and Results: To clarify whether circulating micro RNA s could be used as biomarkers for IA , we carried out microarray assays in a screening cohort of 40 IA patients (20 unruptured and 20 ruptured) and 20 healthy volunteers. We identified 20 micro RNA s that were unanimously changed in both ruptured and unruptured patients. We confirmed 60% of these changed micro RNA s by a separate microarray test with an independent validation cohort (n=143 including 93 IA patients). To identify potential biomarkers, we combined the 2 cohorts and performed quantitative real‐time polymerase chain reactions for selected target micro RNA s. Logistic regression analysis demonstrated that miR‐16 and miR‐25 were independent factors for IA occurrence ( P <0.001). After controlling for age, sex, smoking, and history of hypertension, the contributions of miR‐16 and miR‐25 were still highly significant ( P <0.001). The adjusted odds ratio values for miR‐16 and miR‐25 were 1.52 (95% CI 1.31 to 1.77) and 1.53 (1.30 to 1.79). Combining both miR‐16 and miR‐25 in a single model did not improve the performance of risk association. Conclusions: Our data suggest that circulating mi RNA s may be novel biological markers that are useful in assessing the likelihood of IA occurrence.