CaMKII Is Essential for the Proasthmatic Effects of Oxidation

Sanders, Philip N.; Koval, Olha M.; Jaffer, Omar; Prasad, Anand Mohan; Businga, Thomas R.; Scott, Jason; Hayden, Patrick; Luczak, Elizabeth D.; Dickey, David D.; Allamargot, Chantal; Olivier, Alicia K.; Meyerholz, David K.; Robison, Alfred J.; Winder, Danny G.; Blackwell, Timothy S.; Dworski, Ryszard; Sammut, David; Wagner, Brett A.; Buettner, Garry R.; Pope, R. Marshall; Miller, Francis J.; Dibbern, Megan E.; Haitchi, Hans Michael; Mohler, Peter J.; Howarth, Peter H.; Zabner, Joseph; Kline, Joel N.; Grumbach, Isabella M.; Anderson, Mark E.

doi:10.1126/scitranslmed.3006135

Cited by 62 publications

(96 citation statements)

References 67 publications

(108 reference statements)

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“…Our group originally discovered that CaMKII is activated by ROS (ox-CaMKII) (9) and that ox-CaMKII is increased in airway epithelium from asthmatic patients after allergen exposure where it correlates with asthma severity (8). In subsequent studies, we found that mitochondrial-targeted antioxidant therapy protects against inflammation and fibrosis in OVA-challenged mice (10).…”

Section: Introductionmentioning

confidence: 90%

“…While numerous studies have provided evidence that asthma is a pleiotropic disease marked by increased airway ROS, the molecular mechanisms that connect ROS to asthma phenotypes are uncertain (4)(5)(6)(7). We recently made the unanticipated discovery that the multifunctional Ca 2+ /calmodulin-dependent protein kinase II (CaM-KII) in airway epithelium is a key regulator of the ROS-linked asthmatic phenotypes of inflammation, eosinophilic recruitment and infiltration, and airway hyperreactivity (AHR) in murine models of allergic asthma (8).…”

Section: Introductionmentioning

confidence: 99%

“…We next subjected WT and Mt-CaMKIIN mice to two different validated models of allergic asthma, Aspergillus fumigatus or OVA challenge (Supplemental Figure 2, B and C) (8). We measured airway resistance in response to increasing doses of methacholine.…”

Section: Introductionmentioning

confidence: 99%

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Mitochondrial CaMKII inhibition in airway epithelium protects against allergic asthma

et al. 2017

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Section: Introductionmentioning

confidence: 90%

Section: Introductionmentioning

confidence: 99%

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Mitochondrial CaMKII inhibition in airway epithelium protects against allergic asthma

et al. 2017

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“…Increased OxiCaMKII levels were also detected in OVA challenged allergic asthma mice, compared with vehicle treatment, without any significant increase in total CaMKII levels. Moreover, the Oxi-CaMKII levels were higher in severe asthmatics compared with mild asthmatics and healthy individuals, suggesting that Oxi-CaMKII is not only an indicator of asthma but also a marker of disease severity (61 …”

Section: Oxidative-camkii (Oxi-camkii) Inhibitormentioning

confidence: 99%

“…Oxidative CaMKII was increased in airway epithelium biopsied from mildly asthmatic patients and OVA or aspergillus fumigatus challenged mouse models (61). A mouse model that evaluated airway epithelium with a specific deficiency in CaMKII expression showed clinical features that included inhibition of AHR airway epithelial proliferation and mucus secretion (62).…”

Section: Inflammatory Cellsmentioning

confidence: 99%

Recent developments in the role of reactive oxygen species in allergic asthma

Zhong

et al. 2017

J. Thorac. Dis.

131

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Allergic asthma has a global prevalence, morbidity, and mortality. Many environmental factors, such as pollutants and allergens, are highly relevant to allergic asthma. The most important pathological symptom of allergic asthma is airway inflammation. Accordingly, the unique role of reactive oxygen species It is well known that reactive oxygen species (ROS), endogenous nitric oxide (NO) and NO derived reactive nitrogen species (RNS) have been reported to mediate oxidative stress and airway inflammation and pathogenesis. However, ROS are more common in allergic asthma development (6,7). Hence, in our review, we mainly focus on the relationship between ROS and allergic asthma. ROS, such as hydrogen peroxide, may be directly or indirectly involved in epithelial cell apoptosis and inactivation of antioxidant enzymes and contribute to allergic asthma (8-11). ROS are derived from endogenous or exogenous oxidants. Endogenous ROS are composed of mitochondria, NADPH, and the xanthine/xanthine oxidase (XO) system. Exogenous sources of ROS production have been linked to strong oxidizing gases, such as ozone (O 3 ), sulfur dioxide (SO 2 ), nitrogen dioxide (NO 2 ) and particulate matter (PM), which are a major component of air pollution (12,13). The oxygen stress level in asthma is increased because of inflammatory cells in vivo, and cigarette smoke (CS) or PM produces ROS in vitro. For example, compared with normal subjects, the level of H 2 O 2 and superoxide that are produced by eosinophils and neutrophils are significantly increased in asthma patients (14). Increased levels of ROS can cause harmful pathophysiological disorders of allergic asthma. Studies have reported that excessive ROS can damage DNA, carbohydrates, proteins, and lipids, ultimately leading to an increased inflammatory response in allergic asthma (15,16). In this review, we will discuss the updated pathophysiological and mechanisms of oxidative stress relating to allergic asthma. Exogenous oxidants and allergic asthmaPatients' exposure to the environmental atmosphere is the main way that exogenous oxidative stress is induced (17). CS is a complex mixture including more than 4,000 different compounds. It has been demonstrated that inhaled CS can increase ROS levels. Most of these compounds have ability to generate ROS during their metabolism. The mechanism of CS induced inflammation is incorporated with oxidative stress leading to cell death and oxidative DNA damage via apoptosis and/or necrosis (7). It was reported that antioxidants have the ability to protect cells from cigarette smoke extract (CSE) induced apoptosis (18). Isolated human airway smooth muscle (hASM) cells were used to determine Ca 2+ responses and hASM proliferation, as well as ROS level and cytokine generation, by incubating these cells in the presence or absence of CSE. The results revealed that Ca 2+ regulatory proteins alter airway remolding and function in smoking-related airway disease, especially allergic asthma (19). CSE can damage bronchial epithelial cells from asthm...

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Assessment of the protective effect of KN‐93 drug in systemic epilepsy disorders induced by pilocarpine in male rat

Ebrahimi

Sadr

Roghani

et al. 2019

J of Cellular Biochemistry

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Background and Aims Epileptic seizures occur as a consequence of a sudden imbalance between the stimuli and inhibitors within the network of cortical neurons in favor of the stimulus. One of the drugs that induce epilepsy is pilocarpine. Systemic injection of pilocarpine affects on muscarinic receptors. Increasing evidence has addressed the implication of KN‐93 by blocking Ca2+/calmodulin‐dependent protein kinase II (CaMKII), suppressing oxidative stress and inflammation, and also reducing neuron decay. So, we aimed to evaluate the potential preventive effects of KN‐93 in systemic epilepsy disorders induced by pilocarpine. Materials and Methods In this animal study, male rats were divided into five groups including treatment group (KN‐93 with the dose of 5 mM/10 µL dimethyl sulfoxide (DMSO) before inducing epilepsy by 380 mg/kg pilocarpine) KN‐93 group (received 5 mM KN‐93), control group, epilepsy group (received 380 mg/kg pilocarpine Intraperitoneal), and sham group (received 10 µL DMSO). Oxidative stress was assessed by measuring its indicators including the concentration of malondialdehyde (MDA), nitrite, glutathione (GSH), as well as the antioxidant activity of catalase. In addition, serum levels of proinflammatory mediators including tumor necrosis factor‐α (TNF‐α) and interleukin‐1β (IL‐1β) were determined. Results Pretreatment with KN‐93 significantly reduced oxidative stress index by reducing the concentration of MDA, nitrite, and increasing the level of GSH. In addition, low concentrations of TNF‐α and IL‐1β were observed in hippocampus supernatant of KN‐93 pretreated rats in comparison with the pilocarpine groups. Moreover, administration of KN‐93 improved neuronal density and attenuated the seizure activity and behavior. Conclusions Overall, our findings suggest that KN‐93 can effectively suppress oxidative stress and inflammation. Furthermore, KN‐93 is able to attenuate seizure behaviors by preventing its effects on neuron loss, so, it is valuable for the treatment of epileptic seizures.

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CaMKII Is Essential for the Proasthmatic Effects of Oxidation

Cited by 62 publications

References 67 publications

Mitochondrial CaMKII inhibition in airway epithelium protects against allergic asthma

Mitochondrial CaMKII inhibition in airway epithelium protects against allergic asthma

Recent developments in the role of reactive oxygen species in allergic asthma

Assessment of the protective effect of KN‐93 drug in systemic epilepsy disorders induced by pilocarpine in male rat

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