Hydrogen-Rich Saline Attenuates Brain Injury Induced by Cardiopulmonary Bypass and Inhibits Microvascular Endothelial Cell Apoptosis Via the PI3K/Akt/GSK3β Signaling Pathway in Rats

Background/Aims: Cardiopulmonary bypass (CPB) is prone to inducing brain injury during open heart surgery. A hydrogen-rich solution (HRS) can prevent oxidation and apoptosis, and inhibit inflammation. This study investigated effects of HRS on brain injury induced by CPB and regulatory mechanisms of the PI3K/Akt/GSK3β signaling pathway. Methods: A rat CPB model and an in vitro cell hypoxia model were established. After HRS treatment, Rat behavior was measured using neurological deficit score; Evans blue (EB) was used to assess permeability of the blood-brain barrier (BBB); HE staining was used to observe pathological changes; Inflammatory factors and brain injury markers were detected by ELISA; the PI3K/Akt/GSK3β pathway-related proteins and apoptosis were assessed by western blot, immunohistochemistry and qRT –PCR analyses of brain tissue and neurons. Results: After CPB, brain tissue anatomy was disordered, and cell structure was abnormal. Brain tissue EB content increased. There was an increase in the number of apoptotic cells, an increase in expression of Bax and caspase-3, a decrease in expression of Bcl2, and increases in levels of Akt, GSK3β, P-Akt, and P-GSK3β in brain tissue. HRS treatment attenuated the inflammatory reaction ,brain tissue EB content was significantly reduced and significantly decreased expression levels of Bax, caspase-3, Akt, GSK3β, P-Akt, and P-GSK3β in the brain. After adding the PI3K signaling pathway inhibitor, LY294002, to rat cerebral microvascular endothelial cells (CMECs), HRS could reduce activated Akt expression and downstream regulatory gene phosphorylation of GSK3β expression, and inhibit CMEC apoptosis. Conclusion: The PI3K/Akt/GSK3β signaling pathway plays an important role in the mechanism of CPB-induced brain injury. HRS can reduce CPB-induced brain injury and inhibit CMEC apoptosis through the PI3K/Akt/GSK3β signaling pathway.

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CD28 Deficiency Ameliorates Thoracic Blast Exposure-Induced Oxidative Stress and Apoptosis in the Brain through the PI3K/Nrf2/Keap1 Signaling Pathway

Oxidative Medicine and Cellular Longevity ◽

10.1155/2019/8460290 ◽

2019 ◽

Vol 2019 ◽

pp. 1-14

Author(s):

Peifang Cong ◽

Changci Tong ◽

Ying Liu ◽

Lin Shi ◽

Xiuyun Shi ◽

...

Keyword(s):

Oxidative Stress ◽

Brain Injury ◽

Cytochrome C ◽

Signaling Pathway ◽

Brain Tissue ◽

Caspase 3 ◽

Histopathological Changes ◽

Related Factors ◽

Blast Exposure ◽

The Brain

Blast exposure is a worldwide public health concern, but most related research has been focused on direct injury. Thoracic blast exposure-induced neurotrauma is a type of indirect injuries where research is lacking. As CD28 stimulates T cell activation and survival and contributes to inflammation initiation, it may play a role in thoracic blast exposure-induced neurotrauma. However, it has not been investigated. To explore the effects of CD28 on thoracic blast exposure-induced brain injury and its potential molecular mechanisms, a mouse model of thoracic blast exposure-induced brain injury was established. Fifty C57BL/6 wild-type (WT) and fifty CD28 knockout (CD28-/-) mice were randomly divided into five groups (one control group and four model groups), with ten mice (from each of the two models) for each group. Lung and brain tissue and serum samples were collected at 12 h, 24 h, 48 h, and 1 week after thoracic blast exposure. Histopathological changes were detected by hematoxylin-eosin staining. The expressions of inflammatory-related factors were detected by ELISA. Oxidative stress in the brain tissue was evaluated by determining the generation of reactive oxygen species (ROS) and the expressions of thioredoxin (TRX), malondialdehyde (MDA), SOD-1, and SOD-2. Apoptosis in the brain tissue was evaluated by TUNEL staining and the levels of Bax, Bcl-xL, Bad, Cytochrome C, and caspase-3. In addition, proteins of related pathways were also studied by western blotting and immunofluorescence. We found that CD28 deficiency significantly reduced thoracic blast exposure-induced histopathological changes and decreased the levels of inflammatory-related factors, including IL-1β, TNF-α, and S100β. In the brain tissue, CD28 deficiency also significantly attenuated thoracic blast exposure-induced generation of ROS and expressions of MDA, TRX, SOD-1, and SOD-2; lowered the number of apoptotic cells and the expression of Bax, cleaved caspase-3, Cytochrome C, and Bad; and maintained Bcl-xL expression. Additionally, CD28 deficiency significantly ameliorated thoracic blast exposure-induced increases of p-PI3K and Keap1 and the decrease of Nrf2 expression in the brain. Our results indicate that CD28 deficiency has a protective effect on thoracic blast exposure-induced brain injury that might be associated with the PI3K/Nrf2/Keap1 signaling pathway.

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S-100 B protein and perioperative brain injury in infants and children undergoing open heart surgery using cardiopulmonary bypass

Journal of the Saudi Heart Association ◽

10.1016/j.jsha.2013.03.146 ◽

2013 ◽

Vol 25 (2) ◽

pp. 158-159

Author(s):

Nevin M. Habeeb ◽

Adel Al Ansary ◽

Nermeen Helmy ◽

Omneya Ibrahim Youssef ◽

Nadeen M. Habeeb

Keyword(s):

Cardiopulmonary Bypass ◽

Brain Injury ◽

Heart Surgery ◽

Open Heart Surgery ◽

Infants And Children ◽

Open Heart ◽

S 100 ◽

In Infants And Children

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Forsythiaside-A Alleviates Traumatic Brain Injury by Regulating Toll-Like Receptor 4/Myeloid Differentiation Factor 88/Nuclear Factor-Kappa B Signaling Pathway

Current Topics in Nutraceutical Research ◽

10.37290/ctnr2641-452x.19:326-332 ◽

2021 ◽

Vol 19 (3) ◽

pp. 326-332

Author(s):

Jinsi Tian ◽

Xiaoya Xu ◽

Da Tian

Keyword(s):

Traumatic Brain Injury ◽

Brain Injury ◽

Signaling Pathway ◽

Brain Tissue ◽

Nuclear Factor Kappa B ◽

Myeloid Differentiation ◽

Nuclear Factor ◽

Toll Like Receptor ◽

Toll Like Receptor 4 ◽

Myeloid Differentiation Factor

Traumatic brain injury refers to brain injury caused by mechanical impact often leading to severe morbidity and mortality. Despite increasing awareness, there are no effective treatments strategies. Therefore, there is a need to develop new effective treatments for this injury. Forsythiaside A is a monomer of phenylethanolglucoside extracted from Forsythia, which has a wide range of pharmacological properties including protective effects on brain tissue. Herein, using a rat model of traumatic brain injury, we have shown that forsythiaside A can improve nerve function and brain tissue injury in rats with traumatic brain injury, and reduce brain inflammation and neuronal apoptosis. We have further shown that forsythiaside A regulates toll-like receptor 4/myeloid differentiation factor 88/nuclear factor-kappa B signaling pathway. This opens the possibility of a potentially promising therapeutic drug for the treatment of traumatic brain injury.

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Manual acupuncture relieves microglia-mediated neuroinflammation in a rat model of traumatic brain injury by inhibiting the RhoA/ROCK2 pathway

Acupuncture in Medicine ◽

10.1177/0964528420912248 ◽

2020 ◽

Vol 38 (6) ◽

pp. 426-434

Author(s):

Ming-min Zhu ◽

Ji-huan Lin ◽

Peng Qing ◽

Liu Pu ◽

Shu-lian Chen ◽

...

Keyword(s):

Traumatic Brain Injury ◽

Brain Injury ◽

Signaling Pathway ◽

Inflammatory Factors ◽

Enzyme Linked Immunosorbent Assay ◽

Manual Acupuncture ◽

Sprague Dawley ◽

Tissue Samples ◽

M1 Polarization ◽

Immunofluorescence Labeling

Objective: To investigate the regulatory mechanism of manual acupuncture (MA) on microglial polarization–mediated neuroinflammation after traumatic brain injury (TBI), focusing on the RhoA/Rho-associated coiled coil-forming protein kinase (ROCK2) pathway. Methods: Sprague Dawley (SD) rats were used to generate a TBI model using Feeney’s freefall epidural impact method. MA was performed on half of the TBI model rats, while the others remained untreated. Acupuncture was administered at GV15, GV16, GV20, GV26, and LI4. At the end of the intervention, rat brain tissue samples were collected, and the microglial M1 polarization status was observed by immunofluorescence labeling of CD86, an M1 microglia-specific protein. RhoA/ROCK2 signaling components were detected by quantitative real-time polymerase chain reaction (qRT-PCR) and Western blotting. An enzyme-linked immunosorbent assay (ELISA) was used to detect the expression levels of inflammatory factors. Results: Compared with normal rats, the CD86 expression density in the untreated TBI model rats was high and showed an aggregated expression pattern. The genes and proteins of the RhoA/ROCK2 signaling pathway were highly expressed, and inflammatory factors were significantly increased. The CD86 expression density in TBI rats after MA was reduced compared to that in untreated TBI rats and showed a scattered distribution. The expression of RhoA/ROCK2 signaling pathway genes and proteins was also significantly reduced, and inflammatory factors were decreased. Conclusion: These results show that MA may inhibit M1 polarization of microglia by regulating the RhoA/ROCK2 signaling pathway, thereby reducing neuroinflammation in TBI.

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Activation of alpha-4 beta-2 nicotinic receptor against cardiopulmonary bypass surgery induced brain injury by regulating NLRP3 pathway

10.21203/rs.3.rs-25339/v1 ◽

2020 ◽

Author(s):

Xiuye Liu ◽

Lijuan Yang ◽

Li Wang ◽

Qionghai Guo

Keyword(s):

Cardiopulmonary Bypass ◽

Brain Injury ◽

Brain Tissue ◽

Nicotinic Receptor ◽

Neuronal Apoptosis ◽

Bypass Surgery ◽

Treated Group ◽

Brain Injured ◽

Beta 2 ◽

The Brain

Abstract Present report evaluates the role of alpha-4 beta-2 nicotinic receptor (α4β2 nAChRs) in the development of cardiopulmonary bypass (CPB) surgery induced brain injury. Brain injury was induced by CPB and animals were treated with α4β2 nAChRs agonist (DHβE 9 mg/kg, s.c.) and α4β2 nAChRs antagonist (MLA 10 mg/kg, i.p.) 3 hr before the induction of CPB in the separate groups. Effect of α4β2 nAChRs agonist was determined on the neurological function in CPB induced brain injured rats. Level of cytokines, ROS and expression of NLRP3, ZO-1 and Occluding proteins were estimated in CPB induced brain injured rats. Effect of α4β2 nAChRs agonist was determined on the neuronal apoptosis and histopathological changes in the brain tissue. Result of the study suggest that neurological score was reversed in α4β2 nAChRs agonist treated group than CPB group. Level of cytokines and ROS was reduced in α4β2 nAChRs agonist treated group than CPB group. Neuronal apoptosis in α4β2 nAChRs agonist treated group was found to be reduced compared to CPB group of rats. Moreover Activation of α4β2 nAChRs ameliorates the altered expression of NLRP3, ZO-1 and Occluding protein in the brain tissue of CPB induced brain injured rats. In conclusion, Data of report suggest that treatment with α4β2 nAChRs agonist protects the brain injury in cardiopulmonary bypass surgery induced brain injury by regulating NLRP3 pathway.

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Geniposide Combined With Notoginsenoside R1 Attenuates Inflammation and Apoptosis in Atherosclerosis via the AMPK/mTOR/Nrf2 Signaling Pathway

Frontiers in Pharmacology ◽

10.3389/fphar.2021.687394 ◽

2021 ◽

Vol 12 ◽

Author(s):

Xiaoyu Liu ◽

Yuling Xu ◽

Saibo Cheng ◽

Xinghong Zhou ◽

Fenghua Zhou ◽

...

Keyword(s):

Endothelial Cells ◽

Signaling Pathway ◽

Nlrp3 Inflammasome ◽

Caspase 3 ◽

Blood Lipid ◽

Stress Factors ◽

Inflammatory Factors ◽

Lipid Levels ◽

Nrf2 Signaling Pathway ◽

Blood Lipid Levels

Inflammation and apoptosis of vascular endothelial cells play a key role in the occurrence and development of atherosclerosis (AS), and the AMPK/mTOR/Nrf2 signaling pathway plays an important role in alleviating the symptoms of AS. Geniposide combined with notoginsenoside R1 (GN combination) is a patented supplement for the prevention and treatment of AS. It has been proven to improve blood lipid levels and inhibit the formation of AS plaques; however, it is still unclear whether GN combination can inhibit inflammation and apoptosis in AS by regulating the AMPK/mTOR/Nrf2 signaling pathway and its downstream signals. Our results confirmed that the GN combination could improve blood lipid levels and plaque formation in ApoE−/− mice fed with a high-fat diet (HFD), inhibit the secretion of serum inflammatory factors and oxidative stress factors. It also decreased the expression of pyrin domain containing protein 3 (NLRP3) inflammasome-related protein and Bax/Bcl2/caspase-3 pathway-related proteins. At the same time, the GN combination could also inhibit the H2O2-induced inflammatory response and apoptosis of human umbilical vein endothelial cells (HUVECs), which is mainly related to the activation of the AMPK/mTOR pathway by GN combination, which in turn induces the activation of Nrf2/HO-1 signal. In addition, the above phenomenon could be significantly reversed by dorsomorphin. Therefore, our experiments proved for the first time that the GN combination can effectively inhibit AS inflammation and apoptosis by activating the AMPK/mTOR/Nrf2 signaling pathway to inhibit the NLRP3 inflammasome and Bax/Bcl2/caspase-3 pathway.

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The role of annexin A1 peptide Ac2-26 in regulating PI3K/Akt signaling pathway to reduce lung injury after cardiopulmonary bypass in rats

10.21203/rs.3.rs-391368/v1 ◽

2021 ◽

Author(s):

Yunzi He ◽

Yuanjie Zhang ◽

Hanhua Wu ◽

Junli Luo ◽

Chi Cheng ◽

...

Keyword(s):

Cardiopulmonary Bypass ◽

Lung Injury ◽

Signaling Pathway ◽

Ischemia Reperfusion ◽

Oxygenation Index ◽

Akt Signaling ◽

Inflammatory Factors ◽

Akt Signaling Pathway ◽

The Complement System

Abstract Background: The main causes of lung injury after cardiopulmonary bypass (CPB) are systemic inflammatory response syndrome (SIRS) and lung ischemia–reperfusion (IR) injury. SIRS activates the complement system, releases a variety of inflammatory factors, causes accumulation of neutrophils in the lung tissue, and produces a large amount of oxygen free radicals, which are the main causes of CPB lung injury.Results: Treatment with Ac2-26 improves oxygenation index, reduces the degree of lung pathological damage and lung inflammation, while LY294002 shows the opposite effect. Conclusions: In short, AnxA1 peptide Ac2-26 activates PI3K /Akt signaling pathway, upregulates the phosphorylation levels of PI3K and Akt, inhibits the expression of p-NF-κB(p65), and reduces the release of inflammatory factors and lung injury after CPB in rats.

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RvD1 accelerates the resolution of inflammation by promoting apoptosis of the recruited macrophages via the ALX/FasL-FasR/caspase-3 signaling pathway

Cell Death Discovery ◽

10.1038/s41420-021-00708-5 ◽

2021 ◽

Vol 7 (1) ◽

Author(s):

Shu-yang Xiang ◽

Yang Ye ◽

Qian Yang ◽

Hao- ran Xu ◽

Chen-xi Shen ◽

...

Keyword(s):

Signaling Pathway ◽

Caspase 3 ◽

Distress Syndrome ◽

Inflammatory Factors ◽

Lipid Mediator ◽

Resolvin D1 ◽

Resolution Of Inflammation ◽

Inflammatory Monocytes ◽

Endogenous Lipid ◽

Inflammation Resolution

AbstractThe uncontrolled inflammatory response caused by a disorder in inflammation resolution is one of the reasons for acute respiratory distress syndrome (ARDS). The macrophage pool markedly expands when inflammatory monocytes, known as recruited macrophages, migrate from the circulation to the lung. The persistent presence of recruited macrophages leads to chronic inflammation in the resolution phase of inflammation. On the contrary, elimination of the recruited macrophages at the injury site leads to the rapid resolution of inflammation. Resolvin D1 (RvD1) is an endogenous lipid mediator derived from docosahexaenoic acid. Mice were administered RvD1 via the tail vein 3 and 4 days after stimulation with lipopolysaccharide. RvD1 reduced the levels of the inflammatory factors in the lung tissue, promoted the anti-inflammatory M2 phenotype, and enhanced the phagocytic function of recruited macrophages to alleviate acute lung injury. We also found that the number of macrophages was decreased in BAL fluid after treatment with RvD1. RvD1 increased the apoptosis of recruited macrophages partly via the FasL-FasR/caspase-3 signaling pathway, and this effect could be blocked by Boc-2, an ALX/PRP2 inhibitor. Taken together, our findings reinforce the concept of therapeutic targeting leading to the apoptosis of recruited macrophages. Thus, RvD1 may provide a new therapy for the resolution of ARDS.

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Salt-Inducible Kinase 1 (SIK1) is Induced by Alcohol and Suppresses Microglia Inflammation via NF-κB Signaling

Cellular Physiology and Biochemistry ◽

10.1159/000490831 ◽

2018 ◽

Vol 47 (4) ◽

pp. 1411-1421 ◽

Cited By ~ 8

Author(s):

Yu Zhang ◽

Weida Gao ◽

Kongbin Yang ◽

Haiquan Tao ◽

Haicheng Yang

Keyword(s):

Signaling Pathway ◽

Brain Tissue ◽

Caspase 3 ◽

Tunel Staining ◽

Primary Microglia ◽

Caspase 9 ◽

Inflammatory Processes ◽

Induced Apoptosis ◽

First Time ◽

Crucial Part

Background/Aims: Alcohol consumption has been shown to cause neuroinflammation and increase a variety of immune-related signaling processes. Microglia are a crucial part of alcohol-induced neuroinflammation and undergo apoptosis. Even though the importance of these inflammatory processes in the effects of alcohol-related neurodegeneration have been established, the mechanism of alcohol-induced microglia apoptosis is unknown. In prior research, we discovered that alcohol increases expression of salt-inducible kinase 1 (SIK1) in rodent brain tissue. In this study, we sought to determine what role SIK1 expression plays in alcohol-induced neuroinflammation as well as whether and by what mechanism it regulates microglia apoptosis. Methods: Adult C57BL/6 mice were divided into four groups and for 3 weeks treated with either 0%, 5%, 10%, or 15% alcohol during 3 hour periods. The mice were sacrificed and their brains excised for analysis. Additionally, primary microglia were isolated from neonatal mice. SIK1 expression in alcohol-treated brain tissue and microglia was analyzed via RT-PCR and western blotting. TUNEL staining, caspase-3, and caspase-9 activity assays were performed to evaluate microglial apoptosis. Cell fluorescence staining and NF-κB luciferase activity assays were used to evaluate the effects of SIK1 expression on the NF-κB signaling pathway. Results: SIK1 expression was increased in the brains of mice that consumed alcohol, and this effect was seen in mouse primary microglia. SIK1 knockdown in microglia increased alcohol-induced apoptosis in these cells. Furthermore, SIK1 reduced NF-κB signaling pathway factors, and SIK1 knockdown in microglia promoted alcohol-induced NF-κB activity. TUNEL staining, caspase-3, and caspase-9 activity assays consistently revealed that alcohol-induced microglial apoptosis was inhibited by depletion of p65. Finally, we determined that NF-κB signaling is required for alcohol-induced, SIK1-mediated apoptosis in microglia. Conclusion: This study establishes for the first time not only that SIK1 is crucial to regulating alcohol-induced microglial apoptosis, but also that the NF-κB signaling pathway is required for its activity. Overall, our results help elucidate mechanisms of alcohol-induced neuroinflammation.

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