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Doxorubicin (DOX) is a classic anti-tumor chemotherapeutic used to treat a wide range of tumors. One major downfall of DOX treatment is it can induce fatal cardiotoxicity. Astragaloside IV (AS-IV) is one of the primary active ingredients that can be isolated from the traditional Chinese herbal medicine, Astragalus membranaceus. This study uses both in vitro and in vivo tools to investigate whether AS-IV alleviates DOX induced cardiomyopathy. We found that AS-IV supplementation alleviates body weight loss, myocardial injury, apoptosis of cardiomyocytes, cardiac fibrosis and cardiac dysfunction in DOX-treated mice. Also, DOX-induced cardiomyocyte injury and apoptosis were effectively improved by AS-IV treatment in vitro. NADPH oxidase (NOX) plays an important role in the progress of the oxidative signal transduction and DOX-induced cardiomyopathy. In this study, we found that AS-IV treatment relieves DOX-induced NOX2 and NOX4 expression and oxidative stress in cardiomyocytes. In conclusion, AS-IV, an antioxidant, attenuates DOX-induced cardiomyopathy through the suppression of NOX2 and NOX4., (Copyright © 2019. Published by Elsevier B.V.)

There is evidence to support that ROSs are increased in Parkinson's disease (PD). Our recent research showed that angiotensin II (Ang II) participated in the pathogenesis of PD by triggering oxidative stress. Angiotensin-(1-7)[Ang-(1-7)] has been shown to moderate the adverse effects of the Ang II in many diseases. The purpose of the present study was to determine whether the Ang-(1-7) could have similar effects in CATH.a neurons. We used rotenone-induced neuron injury models to evaluate changes in cultured CATH.a cell lines levels of SOD, GSH and ROS. We also evaluated the expression of AT 1 , AT 2 , Mas receptors and Nox1, Nox2, P47 phox , Hsp70 in treated with PBS, rotenone, Ang-(1-7), or Mas receptor antagonist A-779, alone and combined. The qRT-PCR and western blot were used to detect mRNA and protein levels of the AT 1 , AT 2 , Mas receptors and Nox1, Nox2, P47 phox , Hsp70. The levels of SOD and GSH were determined by using commercial kits. The ROS generation was measured by the fluorescent probe assay. Ang-(1-7) in our current study significantly decreased rotenone-induced oxidative damage and increased the SOD and GSH generation. In addition, Ang-(1-7) significantly elevated Mas receptor expression and reduced NADPH oxidase activation, and these effects were completely eliminated by the A-779. Our findings suggest that Ang-(1-7) attenuates rotenone-induced oxidative damage in CATH.a neurons by activating the Mas receptor expression and inhibiting NADPH oxidase., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

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Background/Aims: An increase in oxidative stress has been implicated in the pathophysiology of pressure-overload induced cardiac hypertrophy. Nobiletin (NOB), extracted from the fruit peel of citrus, possesses anti-oxidative property. Our study aimed to investigate the protective role of NOB in the progression of cardiac hypertrophy in vivo and in vitro. Methods: Mice received aortic banding (AB) operation to induce cardiac hypertrophy. Experimental groups were as follows: sham+vehicle (VEH/SH), sham+NOB (NOB/SH), AB+vehicle (VEH/AB), and AB+ NOB (NOB/AB). Animals (n = 15 per group) were treated with vehicle or NOB (50 mg/kg) for 4 weeks after disease onset. Results: NOB prevented cardiac hypertrophy induced by aortic banding (AB), as assessed by the cross-sectional area of cardiomyocytes, heart weight-to-body weight ratio, gene expression of hypertrophic markers and cardiac function. In addition, NOB supplementation blunted the increased expression of NAPDH oxidase (NOX) 2 and NOX4 and mitigated endoplasmic reticulum (ER) stress and myocyte apoptosis in cardiac hypertrophy. Furthermore, NOB treatment attenuated the neonatal rat cardiomyocyte (NRCM) hypertrophic response stimulated by phenylephrine (PE) and alleviated ER stress. However, our data showed that NOB dramatically inhibited NOX2 expression but not NOX4 in vitro. Finally, we found that knockdown of NOX2 attenuated ER stress in NRCMs stimulated by PE. Conclusions: Inhibition of oxidative and ER stress by NOB in the myocardium may represent a potential therapy for cardiac hypertrophy. Moreover, there is a direct role of NOX2 in regulating ER stress stimulated by PE. [ABSTRACT FROM AUTHOR]

Reactive oxygen species (ROS) are widely involved in intracellular signaling and human pathologies, but their precise roles have been difficult to enumerate and integrate holistically. The context- and dose-dependent intracellular effects of ROS can lead to contradictory experimental results and confounded interpretations. For example, lower levels of ROS promote cell signaling and proliferation, whereas abundant ROS cause overwhelming damage to biomolecules and cellular apoptosis or senescence. These complexities raise the question of whether the many facets of ROS biology can be joined under a common mechanistic framework using computational modeling. Here, we take inventory of some current models for ROS production or ROS regulation of signaling pathways. Several models captured nonintuitive observations or made predictions that were later verified by experiment. There remains a need for systems-level analyses that jointly incorporate ROS production, handling, and modulation of multiple signal-transduction cascades.

Nicotinamide adenine dinucleotide phosphate (NAPDH) oxidase (NOX) is an enzyme complex with the sole function of producing superoxide anion and reactive oxygen species (ROS) at the expense of NADPH. Vital to the immune system as well as cellular signaling, NOX is also involved in the pathologies of a wide variety of disease states. Particularly, it is an integral player in many neurological diseases, including stroke, TBI, and neurodegenerative diseases. Pathologically, NOX produces an excessive amount of ROS that exceed the body's antioxidant ability to neutralize them, leading to oxidative stress and aberrant signaling. This prevalence makes it an attractive therapeutic target and as such, NOX inhibitors have been studied and developed to counter NOX's deleterious effects. However, recent studies of NOX have created a better understanding of the NOX complex. Comprised of independent cytosolic subunits, p47-phox, p67-phox, p40-phox and Rac, and membrane subunits, gp91-phox and p22-phox, the NOX complex requires a unique activation process through subunit interaction. Of these subunits, p47-phox plays the most important role in activation, binding and translocating the cytosolic subunits to the membrane and anchoring to p22-phox to organize the complex for NOX activation and function. Moreover, these interactions, particularly that between p47-phox and p22-phox, are dependent on phosphorylation initiated by upstream processes involving protein kinase C (PKC). This review will look at these interactions between subunits and with PKC. It will focus on the interaction involving p47-phox with p22-phox, key in bringing the cytosolic subunits to the membrane. Furthermore, the implication of these interactions as a target for NOX inhibitors such as apocynin will be discussed as a potential avenue for further investigation, in order to develop more specific NOX inhibitors based on the inhibition of NOX assembly and activation. [ABSTRACT FROM AUTHOR]

Reactive oxygen species (ROS) are widely involved in intracellular signaling and human pathologies, but their precise roles have been difficult to enumerate and integrate holistically. The context- and dose-dependent intracellular effects of ROS can lead to contradictory experimental results and confounded interpretations. For example, lower levels of ROS promote cell signaling and proliferation, whereas abundant ROS cause overwhelming damage to biomolecules and cellular apoptosis or senescence. These complexities raise the question of whether the many facets of ROS biology can be joined under a common mechanistic framework using computational modeling. Here, we take inventory of some current models for ROS production or ROS regulation of signaling pathways. Several models captured non-intuitive observations or made predictions that were later verified by experiment. There remains a need for systemslevel analyses that jointly incorporate ROS production, handling, and modulation of multiple signal-transduction cascades. [ABSTRACT FROM AUTHOR]

Background The angiotensin system has several non-vascular functions in the central nervous system. For instance, inhibition of the brain angiotensin system results in a reduction in neuronal death following acute brain injury such as ischemia and intracerebral hemorrhage, even under conditions of constant blood pressure. Since endogenous zinc has been implicated as a key mediator of ischemic neuronal death, we investigated the possibility that the angiotensin system affects the outcome of zinc-triggered neuronal death in cortical cell cultures. Results Exposure of cortical cultures containing neurons and astrocytes to 300 μM zinc for 15 min induced submaximal death in both types of cells. Interestingly, addition of angiotensin II significantly enhanced the zinc-triggered neuronal death, while leaving astrocytic cell death relatively unchanged. Both type 1 and 2 angiotensin II receptors (AT1R and AT2R, respectively) were expressed in neurons as well as astrocytes. Zinc neurotoxicity was substantially attenuated by PD123319, a specific inhibitor of AT2R, and augmented by CGP42112, a selective activator of AT2R, indicating a critical role for this receptor subtype in the augmentation of neuronal cell death. Because zinc toxicity occurs largely through oxidative stress, the levels of superoxides in zinc-treated neurons were assessed by DCF fluorescence microscopy. Combined treatment with zinc and angiotensin II substantially increased the levels of superoxides in neurons compared to those induced by zinc alone. This increase in oxidative stress by angiotensin II was completely blocked by the addition of PD123319. Finally, since zinc-induced oxidative stress may be caused by induction and/or activation of NADPH oxidase, the activation status of Rac and the level of the NADPH oxidase subunit p67phox were measured. Angiotensin II markedly increased Rac activity and the levels of p67phox in zinc-treated neurons and astrocytes in a PD123319-dependent manner. Conclusion The present study shows that the angiotensin system, especially that involving AT2R, may have an oxidative injury-potentiating effect via augmentation of the activity of NADPH oxidase. Hence, blockade of angiotensin signaling cascades in the brain may prove useful in protecting against the oxidative neuronal death that is likely to occur in acute brain injury. [ABSTRACT FROM AUTHOR]

Background Oxidative stress is involved in progression of left ventricular hypertrophy and heart failure. Since NADPH oxidases are a major source of reactive oxygen species in the heart, we studied left ventricular remodeling after myocardial infarction in mice with targeted deletion of the NADPH oxidase subunit gp91phox. Methods and results gp91phox knockout (KO) and wild-type (WT) animals underwent coronary artery ligation. Mortality was significant higher in the gp91phox KO mice. However, transthoracic echocardiography performed at days 1, 7, and 56 at mid-papillary levels revealed that progression of left ventricular remodeling was not influenced by the genotype. Moreover, systemic oxidative stress was not reduced in gp91phox KO mice as indicated by a significant increase in lipid peroxides potentially mediated by an increase of the NADPH subunit nox-1 in gp91phox KO mice. Conclusion Targeted deletion of the NADPH subunit gp91phox does not affect left ventricular remodeling following myocardial infarction and does not decrease the production of oxidative stress. However, the final role of the different NADPH subunits in the heart under pathophysiologic conditions remains to be determined. [ABSTRACT FROM AUTHOR]

Background Oxidative stress is involved in progression of left ventricular hypertrophy and heart failure. Since NADPH oxidases are a major source of reactive oxygen species in the heart, we studied left ventricular remodeling after myocardial infarction in mice with targeted deletion of the NADPH oxidase subunit gp91phox. Methods and results gp91phox knockout (KO) and wild-type (WT) animals underwent coronary artery ligation. Mortality was significant higher in the gp91phox KO mice. However, transthoracic echocardiography performed at days 1, 7, and 56 at mid-papillary levels revealed that progression of left ventricular remodeling was not influenced by the genotype. Moreover, systemic oxidative stress was not reduced in gp91phox KO mice as indicated by a significant increase in lipid peroxides potentially mediated by an increase of the NADPH subunit nox-1 in gp91phox KO mice. Conclusion Targeted deletion of the NADPH subunit gp91phox does not affect left ventricular remodeling following myocardial infarction and does not decrease the production of oxidative stress. However, the final role of the different NADPH subunits in the heart under pathophysiologic conditions remains to be determined. [ABSTRACT FROM AUTHOR]