Sepsis-induced brain mitochondrial dysfunction is associated with altered mitochondrial Src and PTP1B levels

Lyu, Jingjing; Zheng, Guilang; Chen, Zhijiang; Wang, Bin; Shen, Tao; Xiang, Dan; Xie, Meiyan; Huang, Jinda; Liu, Cui; Zeng, Quan

doi:10.1016/j.brainres.2015.04.062

Cited by 21 publications

(19 citation statements)

References 31 publications

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“…The pathogenesis of sepsis-induced brain dysfunction is associated with mitochondrial dysfunction (Bozza et al 2013;Lyu et al 2015;Wang et al 2014). In a rat model of LPS-induced SAE, mitochondrial dysfunction was found to be associated with altered mitochondrial tyrosine kinase Src and protein phosphatase 1B (PTP1B) levels (Lyu et al 2015). In the same study, pretreatment of mitochondrial proteins with active PTP1B resulted in overproduction of ROS and decreased mitochondrial membrane potential (Lyu et al 2015).…”

Section: Discussionmentioning

confidence: 99%

“…In a rat model of LPS-induced SAE, mitochondrial dysfunction was found to be associated with altered mitochondrial tyrosine kinase Src and protein phosphatase 1B (PTP1B) levels (Lyu et al 2015). In the same study, pretreatment of mitochondrial proteins with active PTP1B resulted in overproduction of ROS and decreased mitochondrial membrane potential (Lyu et al 2015). In a CLP-induced SAE mouse model, it was found that the mitochondrial function of the hippocampus was severely impaired, coupled with increased ROS, neuronal apoptosis and inflammation (Wu et al 2015).…”

Section: Discussionmentioning

confidence: 99%

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Assessing long-term neuroinflammatory responses to encephalopathy using MRI approaches in a rat endotoxemia model

et al. 2018

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Sepsis-associated encephalopathy (SAE) induces neuroinflammation, which is associated with cognitive impairment (CI). CI is also correlated with aging. We used contrast-enhanced magnetic resonance imaging (MRI), perfusion MRI, and MR spectroscopy to assess long-term alterations in BBB permeability, microvascularity, and metabolism, respectively, in a rat lipopolysaccharide-induced SAE model. Free radical-targeted molecular MRI was used to detect brain radical levels at 24 h and 1 week post-LPS injection. CE-MRI showed increased Gd-DTPA uptake in LPS rat brains at 24 h in cerebral cortex, hippocampus, thalamus, and perirhinal cortex regions. Increased MRI signal intensities were observed in LPS rat brains in cerebral cortex, perirhinal cortex, and hippocampus regions 1 week post-LPS. Long-term BBB dysfunction was detected in the cerebral cortex at 6 weeks post-LPS. Increased relative cerebral blood flow (rCBF) in cortex and thalamus regions at 24 h, decreased cortical and hippocampal rCBF at 6 weeks, decreased cortical rCBF at 3 and 12 weeks, and increased thalamus rCBF at 6 weeks post-LPS, were detected. MRS indicated that LPS-exposed rat brains had decreased: NAA/Cho metabolite ratios at 1, 3, 6, and 12 weeks; Cr/Cho at 1, 3, and 12 weeks; and Myo-Ins/Cho at 1, 3, and 6 weeks post-LPS. Free radical imaging detected increased radical levels in LPS rat brains at 24 h and 1 week post-LPS. LPS-exposed rats were compared to saline-treated controls. We clearly demonstrated BBB dysfunction, impaired vascularity, and decreased brain metabolites, as measures of long-term neuroinflammatory indicators, as well as increased free radicals in a LPS-induced rat SAE model.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Assessing long-term neuroinflammatory responses to encephalopathy using MRI approaches in a rat endotoxemia model

et al. 2018

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“…It is well established that systemic inflammation induces mitochondrial dysfunction, which leads to oxidative stress (Bozza et al 2013;Lyu et al 2015;Wang et al 2014;Berg et al 2011). Mitochondrial dysfunction was found to be associated with altered mitochondrial tyrosine kinase Src and protein phosphatase 1B (PTP1B) levels in a rat model of LPS-induced SAE (Lyu et al 2015). In the same study, pretreatment of mitochondrial proteins with active PTP1B resulted in overproduction of ROS and decreased mitochondrial membrane potential (Lyu et al 2015).…”

Section: Discussionmentioning

confidence: 99%

“…Mitochondrial dysfunction was found to be associated with altered mitochondrial tyrosine kinase Src and protein phosphatase 1B (PTP1B) levels in a rat model of LPS-induced SAE (Lyu et al 2015). In the same study, pretreatment of mitochondrial proteins with active PTP1B resulted in overproduction of ROS and decreased mitochondrial membrane potential (Lyu et al 2015). It was also found that the mitochondrial function of the hippocampus was severely impaired, coupled with increased ROS, neuronal apoptosis, and inflammation, in a CLP-induced SAE mouse model (Wu et al 2015).…”

Section: Discussionmentioning

confidence: 99%

Anti-inflammatory agent, OKN-007, reverses long-term neuroinflammatory responses in a rat encephalopathy model as assessed by multi-parametric MRI: implications for aging-associated neuroinflammation

et al. 2019

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Lipopolysaccharide (LPS)-induced encephalopathy induces neuroinflammation. Long-term neuroinflammation is associated with aging and subsequent cognitive impairment (CI). We treated rats that had LPSinduced neuroinflammation with OKN-007, with an anti-inflammatory agent currently considered an anticancer investigational new drug in clinical trials for glioblastoma (GBM). Contrast-enhanced magnetic resonance imaging (MRI) (CE-MRI), perfusion MRI, and MR spectroscopy were used as methods to assess longterm (up to 6 weeks post-LPS) alterations in blood-brain barrier (BBB) permeability, microvascularity, and metabolism, respectively, and the therapeutic effect of OKN-007. A free radical-targeted molecular MRI approach was also used to detect the effect of OKN-007 on brain free radical levels at 24 h and 1 week post-LPS injection. OKN-007 was able to reduce BBB permeability in the cerebral cortex and hippocampus at 1 week post-LPS using CE-MRI. OKN-007 was able to restore vascular perfusion rates by reducing LPS-induced increased relative cerebral blood flow (rCBF) in the cortex and hippocampus regions at all time points studied (1, 3, and 6 weeks post-LPS). OKN-007 was also able to restore LPS-induced brain metabolite depletions. NAA/Cho, Cr/Cho, and Myo-Ins/Cho metabolite ratios at 1, 3, and 6 weeks post-LPS were all restored to normal levels following OKN-007 treatment. OKN-007 also reduced LPS-induced free radical levels at 24 h and 1 week post-LPS, as detected by free radicaltargeted MRI. LPS-exposed rats were compared with saline-treated controls and LPS + OKN-007-treated animals. We clearly demonstrated that OKN-007 restores LPS-induced BBB dysfunction, impaired vascularity, and decreased brain metabolites, all long-term neuroinflammatory indicators, as well as decreases free radicals in a LPS-induced neuroinflammation model. OKN-007 should be considered an anti-inflammatory agent for age-associated neuroinflammation.

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“…The heart is an organ rich in mitochondria, and the mitochondrial dysfunction in sepsis is therefore receiving increasing attention [4]. Studies have shown that many factors are associated with the development of myocardial damage in sepsis, such as excessive production of ROS and destruction of mitochondrial membrane potential [5, 6]; however, the specific underlying mechanism of myocardial damage in patients with sepsis remains unclear. Gram-negative bacteria which could secrete lipopolysaccharide are the main pathogens that induce sepsis.…”

Section: Introductionmentioning

confidence: 99%

Adenosine Attenuates LPS-Induced Cardiac Dysfunction by Inhibition of Mitochondrial Function via the ER Pathway

Zeng

Zhang

et al. 2019

Evidence-Based Complementary and Alternative Medicine

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Sepsis is a life-threatening organ dysfunction syndrome with a high rate of mortality. It is caused by an abnormal immune response to infection, and the occurrence of sepsis-induced cardiomyopathy is the primary cause of death. The present study was designed to examine the effects of adenosine on lipopolysaccharide- (LPS-) induced cardiac anomalies and the underlying mechanisms involved. Adenosine (25, 50, and 100 mg/kg, i.g., 2 times/day) was administered for three days, followed by the induction of sepsis by intraperitoneal injection of LPS (10 mg/kg/2h). The effects of adenosine on inflammatory factors, LVEF, LVFS, and MAPK in septic rats (half male and half female) were observed. Subsequently, the effect of adenosine (10 μM) on the mitochondrial function of H9c2 cells stimulated with LPS (20 μg/mL, 24 h) was observed in the presence and absence of the estrogen receptor-specific antagonist ICI182,780. The results show that medium to high doses of adenosine can significantly promote cardiac function (LVEF and LVFS) and reduce the levels of inflammatory factors (TNF-α, IL-6, PCT, and cTnI) and p-JNK in septic rats, with a significant difference seen between male and female rats. The results of flow cytometry show that adenosine significantly inhibited increases in ROS levels, mitochondrial membrane potential, and the swelling degree of mitochondria in H9c2 cells stimulated with LPS, but this effect could be blocked by ICI182,780, indicating that adenosine attenuated LPS-induced cardiac dysfunction by inhibiting mitochondrial function via the ER pathway.

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Sepsis-induced brain mitochondrial dysfunction is associated with altered mitochondrial Src and PTP1B levels

Cited by 21 publications

References 31 publications

Assessing long-term neuroinflammatory responses to encephalopathy using MRI approaches in a rat endotoxemia model

Assessing long-term neuroinflammatory responses to encephalopathy using MRI approaches in a rat endotoxemia model

Anti-inflammatory agent, OKN-007, reverses long-term neuroinflammatory responses in a rat encephalopathy model as assessed by multi-parametric MRI: implications for aging-associated neuroinflammation

Adenosine Attenuates LPS-Induced Cardiac Dysfunction by Inhibition of Mitochondrial Function via the ER Pathway

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