Role of <scp>NADPH</scp> Oxidase in Total Salvianolic Acid Injection Attenuating Ischemia‐Reperfusion Impaired Cerebral Microcirculation and Neurons: Implication of <scp>AMPK</scp>/Akt/<scp>PKC</scp>

Tang, Hao; Pan, Chun‐Shui; Mao, Xiaowei; Liu, Yuying; Li, Yan; Zhou, Changman; Fan, Jing‐Yu; Zhang, Shuangyan; Han, Jing‐Yan

doi:10.1111/micc.12140

Cited by 48 publications

(34 citation statements)

References 34 publications

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“…Lastly, our data that activation of AMPK by metformin inhibits LPS‐induced gp91 phox upregulation indicate that LPS increases gp91 phox through regulating AMPK. This result is consistent with previous reports in which AMPK has been shown to regulate NADPH oxidase (Song & Zou, ; Ou et al ., ; Tang et al ., ). As an example, AMPKα2 has been reported to function as a physiological suppressor of NADPH oxidase and ROS production in endothelial cells, and its deletion causes aberrant expression and activation of NADPH oxidase and consequent endothelial dysfunction in vivo (Wang et al ., ).…”

Section: Discussionmentioning

confidence: 97%

Melatonin alleviates lipopolysaccharide-compromised integrity of blood-brain barrier through activating AMP-activated protein kinase in old mice

et al. 2017

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SummaryBlood–brain barrier (BBB) dysfunction is considered to be an early event in the pathogenesis of a variety of neurological diseases in old patients, and this could occur in old people even when facing common stress. However, the mechanism remains to be defined. In this study, we tested the hypothesis that decreased melatonin levels may account for the BBB disruption in old mice challenged with lipopolysaccharide (LPS), which mimicked the common stress of sepsis. Mice (24–28 months of age) received melatonin (10 mg kg−1 day−1, intraperitoneally, i.p.) or saline for one week before exposing to LPS (1 mg kg−1, i.p.). Evan's blue dye (EB) and immunoglobulin G (IgG) leakage were used to assess BBB permeability. Immunostaining and Western blot were used to detect protein expression and distribution. Our results showed that LPS significantly increased BBB permeability in old mice accompanied by the degradation of tight junction proteins occludin and claudin‐5, suppressed AMP‐activated protein kinase (AMPK) activation, and elevated gp91phox protein expression. Interestingly, administration of melatonin for one week significantly decreased LPS‐induced BBB disruption, AMPK suppression, and gp91phox upregualtion. Moreover, activation of AMPK with metformin significantly inhibited LPS‐induced gp91phox upregualtion in endothelial cells. Taken together, our findings demonstrate that melatonin alleviates LPS‐induced BBB disruption through activating AMPK and inhibiting gp91phox upregulation in old mice.

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Section: Discussionmentioning

confidence: 97%

Melatonin alleviates lipopolysaccharide-compromised integrity of blood-brain barrier through activating AMP-activated protein kinase in old mice

et al. 2017

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“…Through its use, AMPK expression is enhanced, resulting in the subsequent observed reduction of AKT activation, PKC translocation to the membrane, and overall NOX activation with the failure of migration of the cytosolic subunits to the membrane. It acts via the AMPK/AKT/PKC signaling pathway (Tang et al, 2014). By defining the pathological upstream activators of NOX in specific disease states, NOX inhibition can be facilitated by targeting these upstream players, such as PKC and ANGII.…”

Section: Potential Treatments On Nox Activationmentioning

confidence: 99%

NOX Activation by Subunit Interaction and Underlying Mechanisms in Disease

Rastogi

et al. 2017

Front. Cell. Neurosci.

174

167

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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.

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“…SA, consists of the water-soluble components isolated from the roots of Salvia miltiorrhiza Bunge, which contains 1% SA A, 57% SA B, 37% rosmarinic acid and 5% other acids, and is a Chinese herb widely used for the treatment of stroke (40). The use of SA was approved in 2011 by the Chinese State food and Drug administration (Z20110011) for the treatment of ischemic stroke (41). Previous findings have indicated that SA inhibits lipid peroxidation, scavenges free radicals and protects neural cells against injuries caused by anoxia (42,43).…”

Section: Discussionmentioning

confidence: 99%

Effects of salvianolic acid on cerebral perfusion in patients after acute stroke: A single‑center randomized controlled trial

et al. 2018

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Hypoperfusion following acute stroke is common in the infarct core and periphery tissues. The present study evaluated the efficacy of salvianolic acid (SA) on the cerebral perfusion of patients who had suffered from acute stroke using perfusion-weighted magnetic resonance imaging (PWI) to examine the blood perfusion of the affected brain tissue prior to and following treatment. Patients who were admitted to PLA 153 Central Hospital within 72 h of acute stroke symptom onset and had a Glasgow coma scale ≥5 were randomized into two groups: SA and control groups. Patients in the SA group were administered SA 0.13 g/day for 14 days. PWI was performed for all patients at admission and post-treatment. The National Institutes of Health Stroke Scale (NIHSS) and modified Rankin Scale (mRS) were applied to assess neurological function at admission and 3 months post treatment. A total of 159 patients were enrolled (85 patients in the SA group and 74 patients in the control group). A total of 62 patients in the SA group and 51 patients in the control group exhibited hypoperfusion in the ipsihemisphere of the diffusion-weighted magnetic resonance imaging (DWI) lesion. In addition, relative cerebral blood volume (rCBV), a ratio of the signal value of the region of interest in the same hemisphere of the DWI lesion to that of its mirror in the PWI CBV map, decreased significantly following treatment with SA compared with the control group in patients with hypoperfusion (P=0.02), which were indicated by PWI images at admission, in the DWI lesions or the surrounding areas. Additionally, there was no significant difference in patients with normal perfusion at admission in rCBV in DWI lesions or its surrounding area between the two groups at day 15. However, a significant improvement in NIHSS (P=0.001) and mRS (P=0.005) was indicated in the SA group compared with the control at day 90. The present study indicated that SA may improve the neurological dysfunction of patients with acute stroke, which may be explained by the increased perfusion of hypoperfused brain tissues.

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Role of NADPH Oxidase in Total Salvianolic Acid Injection Attenuating Ischemia‐Reperfusion Impaired Cerebral Microcirculation and Neurons: Implication of AMPK/Akt/PKC

Cited by 48 publications

References 34 publications

Melatonin alleviates lipopolysaccharide-compromised integrity of blood-brain barrier through activating AMP-activated protein kinase in old mice

Melatonin alleviates lipopolysaccharide-compromised integrity of blood-brain barrier through activating AMP-activated protein kinase in old mice

NOX Activation by Subunit Interaction and Underlying Mechanisms in Disease

Effects of salvianolic acid on cerebral perfusion in patients after acute stroke: A single‑center randomized controlled trial

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