Abstract 3602: Inhibition of Soluble Epoxide Hydrolase Improves Neuronal Survival after Cardiac Arrest and Alters Microglial Activation towards a Neuroprotective Phenotype

Stroke ◽  
2012 ◽  
Vol 43 (suppl_1) ◽  
Author(s):  
Jianming Wang ◽  
Tetsuhiro Fujiyoshi ◽  
Yasuharu Kosaka ◽  
Paco S Herson ◽  
Ines P Koerner
Keyword(s):  
Cardiac Arrest ◽  
Brain Injury ◽  
Inflammatory Cytokines ◽  
Neuronal Death ◽  
Epoxide Hydrolase ◽  
Microglial Activation ◽  
Soluble Epoxide Hydrolase ◽  
Functional Deficit ◽  
Tnf Α ◽  
Pro Inflammatory Cytokines

Introduction: Ischemia/reperfusion during cardiac arrest and cardiopulmonary resuscitation (CA/CPR) causes significant neuronal death and leads to long-term functional deficits. While neuronal death in the hippocampus is one likely cause of memory loss after CA/CPR, the local inflammatory milieu present after CA/CPR also contributes to functional deficit. However, the signaling pathways involved in the inflammatory response are poorly understood. Microglia, the brain resident immune cells, are activated in response to different types of brain injury. We hypothesized that CA/CPR activates microglia, which then contribute to subsequent neuronal loss and functional deficit. We tested whether pharmacologic inhibition of the pro-inflammatory enzyme soluble epoxide hydrolase (sEH) alters microglial activation and neuronal death in a mouse model of CA/CPR. Methods: Male adult C57Bl/6 mice underwent 8 minutes of CA followed by CPR. The sEH inhibitor 4-phenylchalcone oxide (4-PCO; 5 mg/kg ip) was administered at 5 minutes and 24 hours after CA/CPR. Microglial activation was assessed histologically by immunostaining for the activation marker Mac-2 at 24 and 72 hours after CA/CPR. Surviving CA1 hippocampal neurons were counted at 72 hours after CA/CPR. Hippocampal expression of inflammatory cytokines was measured by quantitative RT-PCR. Results: Phenotypically activated microglia expressing Mac-2 appeared in the hippocampus as early as 24 hours after CA/CPR, before significant neuronal death was present. Concurrently, expression of the pro-inflammatory cytokines tumor necrosis factor (TNF)-α and interleukin (IL)-1β increased. In animals treated with 4-PCO, hippocampal expression of the anti-inflammatory cytokine IL-10 was significantly increased (2-fold vs. vehicle), while expression of pro-inflammatory TNF- α and IL-1 β was unchanged. Subsequent death of CA1 neurons at 72 hours after CA/CPR was significantly reduced in animals treated with 4-PCO (34+/-3.7% 4-PCO vs. 52+/-7.1% vehicle), whereas the number of Mac-2 positive microglia was unchanged. Conclusions: Microglia are activated and produce pro-inflammatory cytokines early after CA/CPR. Inhibition of sEH induces hippocampal expression of anti-inflammatory and neuroprotective IL-10 and reduces subsequent neuronal death after CA/CPR, without altering the number of phenotypically activated Mac-2 positive microglia or expression of pro-inflammatory cytokines in the hippocampus. This suggests that sEH inhibition may alter gene expression in activated microglia after brain ischemia, thus protecting neurons and maintaining function. IL-10 induction by sEH inhibition is a promising therapeutic approach after ischemic brain injury from CA/CPR.

scholarly journals Phosphoglycerate Mutase 1 Prevents Neuronal Death from Ischemic Damage by Reducing Neuroinflammation in the Rabbit Spinal Cord

2020 ◽  
Vol 21 (19) ◽  
pp. 7425
Author(s):  
Hyo Young Jung ◽  
Hyun Jung Kwon ◽  
Woosuk Kim ◽  
Kyu Ri Hahn ◽  
Seung Myung Moon ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Spinal Cord ◽  
Inflammatory Cytokines ◽  
Neuronal Death ◽  
Microglial Activation ◽  
Ventral Horn ◽  
Phosphoglycerate Mutase ◽  
Ischemic Damage ◽  
Tnf Α ◽  
Pro Inflammatory Cytokines

Phosphoglycerate mutase 1 (PGAM1) is a glycolytic enzyme that increases glycolytic flux in the brain. In the present study, we examined the effects of PGAM1 in conditions of oxidative stress and ischemic damage in motor neuron-like (NSC34) cells and the rabbit spinal cord. A Tat-PGAM1 fusion protein was prepared to allow easy crossing of the blood-brain barrier, and Control-PGAM1 was synthesized without the Tat peptide protein transduction domain. Intracellular delivery of Tat-PGAM1, not Control-PGAM1, was achieved in a time- and concentration-dependent manner. Immunofluorescent staining confirmed the intracellular expression of Tat-PGAM1 in NSC34 cells. Tat-PGAM1, but not Control-PGAM1, significantly alleviated H2O2-induced oxidative stress, neuronal death, mitogen-activated protein kinase, and apoptosis-inducing factor expression in NSC34 cells. After ischemia induction in the spinal cord, Tat-PGAM1 treatment significantly improved ischemia-induced neurological impairments and ameliorated neuronal cell death in the ventral horn of the spinal cord 72 h after ischemia. Tat-PGAM1 treatment significantly mitigated the ischemia-induced increase in malondialdehyde and 8-iso-prostaglandin F2α production in the spinal cord. In addition, Tat-PGAM1, but not Control-PGAM1, significantly decreased microglial activation and secretion of pro-inflammatory cytokines, such as interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α induced by ischemia in the ventral horn of the spinal cord. These results suggest that Tat-PGAM1 can be used as a therapeutic agent to reduce spinal cord ischemia-induced neuronal damage by lowering the oxidative stress, microglial activation, and secretion of pro-inflammatory cytokines, such as IL-1β, IL-6, and TNF-α.

scholarly journals Inhibition of Soluble Epoxide Hydrolase after Cardiac Arrest/Cardiopulmonary Resuscitation Induces a Neuroprotective Phenotype in Activated Microglia and Improves Neuronal Survival

2013 ◽  
Vol 33 (10) ◽  
pp. 1574-1581 ◽  
Author(s):  
Jianming Wang ◽  
Tetsuhiro Fujiyoshi ◽  
Yasuharu Kosaka ◽  
Jonathan D Raybuck ◽  
K Matthew Lattal ◽  
...  
Keyword(s):  
Cardiac Arrest ◽  
Cardiopulmonary Resuscitation ◽  
Neuronal Death ◽  
Epoxide Hydrolase ◽  
Memory Function ◽  
Specific Treatment ◽  
Neuronal Loss ◽  
Soluble Epoxide Hydrolase ◽  
Activated Microglia ◽  
Tnf Α

Cardiac arrest (CA) causes hippocampal neuronal death that frequently leads to severe loss of memory function in survivors. No specific treatment is available to reduce neuronal death and improve functional outcome. The brain's inflammatory response to ischemia can exacerbate injury and provides a potential treatment target. We hypothesized that microglia are activated by CA and contribute to neuronal loss. We used a mouse model to determine whether pharmacologic inhibition of the proinflammatory microglial enzyme soluble epoxide hydrolase (sEH) after CA alters microglial activation and neuronal death. The sEH inhibitor 4-phenylchalcone oxide (4-PCO) was administered after successful cardiopulmonary resuscitation (CPR). The 4-PCO treatment significantly reduced neuronal death and improved memory function after CA/CPR. We found early activation of microglia and increased expression of inflammatory tumor necrosis factor (TNF)-α and interleukin (IL)-1β in the hippocampus after CA/CPR, which was unchanged after 4-PCO treatment, while expression of antiinflammatory IL-10 increased significantly. We conclude that sEH inhibition after CA/CPR can alter the transcription profile in activated microglia to selectively induce antiinflammatory and neuroprotective IL-10 and reduce subsequent neuronal death. Switching microglial gene expression toward a neuroprotective phenotype is a promising new therapeutic approach for ischemic brain injury.

Abstract P31: The Central Nervous System’s Inflammatory Cytokine Response to Global Ischemia Due to Cardiac Arrest

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Scott Youngquist ◽  
James T Niemann ◽  
Ted Heyming ◽  
John P Rosborough
Keyword(s):  
Cardiac Arrest ◽  
Inflammatory Cytokines ◽  
Porcine Model ◽  
Rank Correlation ◽  
Small Animal ◽  
Cytokine Response ◽  
Hypoxic Ischemia ◽  
Tnf Α ◽  
Csf Levels ◽  
Pro Inflammatory Cytokines

Objective: Pro-inflammatory cytokines have been implicated as culprits in neurotoxicity following ischemia in small animal models of stroke. The aim of this study was to measure the central nervous system (CNS) cytokine response following resuscitation from ventricular fibrillation (VF) in a porcine model of cardiac arrest and global hypoxic ischemia. Methods: VF was induced electrically in eleven anesthetized swine. Following seven minutes of untreated VF, animals were resuscitated. Cerebrospinal fluid (CSF) and serum was sampled prior to VF and at 60, 120, and 180 minutes post-resuscitation from which levels of TNF-α IL-1β, and IL-6 were measured. Levels were also drawn in three sham pigs, instrumented but not fibrillated. Results: CSF levels of TNF-α rose following resuscitation (p<0.0001, FIGURE ) and were correlated with CSF levels of IL-1β (Spearman rank correlation r=0.68, p<0.0001) and IL-6 (r=0.55, p=0.0003). Changes in cytokine levels were not observed in sham pigs. Only CSF levels of IL-1β were associated with its serum counterpart (p=0.0006). Conclusions: Measurable increases in pro-inflammatory cytokines in the CSF follow resuscitation from cardiac arrest in this porcine model. The CNS response of all three inflammatory cytokines is highly inter-correlated.

Inhibition of Pro-Inflammatory Cytokine Secretion by Select Antioxidants in Human Coronary Artery Endothelial Cells

2020 ◽  
Vol 90 (1-2) ◽  
pp. 103-112 ◽  
Author(s):  
Michael J. Haas ◽  
Marilu Jurado-Flores ◽  
Ramadan Hammoud ◽  
Victoria Feng ◽  
Krista Gonzales ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Ascorbic Acid ◽  
Coronary Artery ◽  
Inflammatory Cytokines ◽  
Inflammatory Cytokine ◽  
Culture Media ◽  
Cytokine Secretion ◽  
Human Coronary Artery ◽  
Tnf Α ◽  
Pro Inflammatory Cytokines

Abstract. Inflammatory and oxidative stress in endothelial cells are implicated in the pathogenesis of premature atherosclerosis in diabetes. To determine whether high-dextrose concentrations induce the expression of pro-inflammatory cytokines, human coronary artery endothelial cells (HCAEC) were exposed to either 5.5 or 27.5 mM dextrose for 24-hours and interleukin-1β (IL-1β), interleukin-2 (IL-2), interleukin-6 (IL-6), interleukin-8 (IL-8), and tumor necrosis factor α (TNF α) levels were measured by enzyme immunoassays. To determine the effect of antioxidants on inflammatory cytokine secretion, cells were also treated with α-tocopherol, ascorbic acid, and the glutathione peroxidase mimetic ebselen. Only the concentration of IL-1β in culture media from cells exposed to 27.5 mM dextrose increased relative to cells maintained in 5.5 mM dextrose. Treatment with α-tocopherol (10, 100, and 1,000 μM) and ascorbic acid (15, 150, and 1,500 μM) at the same time that the dextrose was added reduced IL-1β, IL-6, and IL-8 levels in culture media from cells maintained at 5.5 mM dextrose but had no effect on IL-1β, IL-6, and IL-8 levels in cells exposed to 27.5 mM dextrose. However, ebselen treatment reduced IL-1β, IL-6, and IL-8 levels in cells maintained in either 5.5 or 27.5 mM dextrose. IL-2 and TNF α concentrations in culture media were below the limit of detection under all experimental conditions studied suggesting that these cells may not synthesize detectable quantities of these cytokines. These results suggest that dextrose at certain concentrations may increase IL-1β levels and that antioxidants have differential effects on suppressing the secretion of pro-inflammatory cytokines in HCAEC.

scholarly journals Punicalagin Prevents Inflammation in LPS-Induced RAW264.7 Macrophages by Inhibiting FoxO3a/Autophagy Signaling Pathway

Nutrients ◽  
2019 ◽  
Vol 11 (11) ◽  
pp. 2794 ◽  
Author(s):  
Cao ◽  
Chen ◽  
Ren ◽  
Zhang ◽  
Tan ◽  
...  
Keyword(s):  
Western Blot ◽  
Signaling Pathway ◽  
Inflammatory Cytokines ◽  
Blot Analysis ◽  
Western Blot Analysis ◽  
Inflammatory Responses ◽  
Raw264.7 Macrophages ◽  
Tnf Α ◽  
Autophagy Inhibition ◽  
Pro Inflammatory Cytokines

Punicalagin, a hydrolysable tannin of pomegranate juice, exhibits multiple biological effects, including inhibiting production of pro-inflammatory cytokines in macrophages. Autophagy, an intracellular self-digestion process, has been recently shown to regulate inflammatory responses. In this study, we investigated the anti-inflammatory potential of punicalagin in lipopolysaccharide (LPS) induced RAW264.7 macrophages and uncovered the underlying mechanisms. Punicalagin significantly attenuated, in a concentration-dependent manner, LPS-induced release of NO and decreased pro-inflammatory cytokines TNF-α and IL-6 release at the highest concentration. We found that punicalagin inhibited NF-κB and MAPK activation in LPS-induced RAW264.7 macrophages. Western blot analysis revealed that punicalagin pre-treatment enhanced LC3II, p62 expression, and decreased Beclin1 expression in LPS-induced macrophages. MDC assays were used to determine the autophagic process and the results worked in concert with Western blot analysis. In addition, our observations indicated that LPS-induced releases of NO, TNF-α, and IL-6 were attenuated by treatment with autophagy inhibitor chloroquine, suggesting that autophagy inhibition participated in anti-inflammatory effect. We also found that punicalagin downregulated FoxO3a expression, resulting in autophagy inhibition. Overall these results suggested that punicalagin played an important role in the attenuation of LPS-induced inflammatory responses in RAW264.7 macrophages and that the mechanisms involved downregulation of the FoxO3a/autophagy signaling pathway.

scholarly journals Modulation of ACE-2 mRNA by inflammatory cytokines in human thyroid cells: a pilot study

Endocrine ◽  
2021 ◽  
Author(s):  
Francesca Coperchini ◽  
Gianluca Ricci ◽  
Laura Croce ◽  
Marco Denegri ◽  
Rubina Ruggiero ◽  
...  
Keyword(s):  
Inflammatory Cytokines ◽  
Combination Treatment ◽  
Primary Cultures ◽  
Human Thyroid ◽  
Thyroid Cell ◽  
Mrna Levels ◽  
Thyroid Cells ◽  
Tnf Α ◽  
Ifn Γ ◽  
Pro Inflammatory Cytokines

Abstract Introduction Angiotensin-converting-enzyme-2 (ACE-2) was demonstrated to be the receptor for cellular entry of SARS-CoV-2. ACE-2 mRNA was identified in several human tissues and recently also in thyroid cells in vitro. Purpose Aim of the present study was to investigate the effect of pro-inflammatory cytokines on the ACE-2 mRNA levels in human thyroid cells in primary cultures. Methods Primary thyroid cell cultures were treated with IFN-γ and TNF-α alone or in combination for 24 h. ACE-2 mRNA levels were measured by RT-PCR. As a control, the levels of IFN-γ inducible chemokine (CXCL10) were measured in the respective cell culture supernatants. Results The mean levels of ACE-2 mRNA increased after treatment with IFN-γ and TNF-α in all the thyroid cell preparations, while the combination treatment did not consistently synergically increase ACE-2-mRNA. At difference, CXCL10 was consistently increased by IFN-γ and synergically further increased by the combination treatment with IFN-γ + TNF-α, with respect to IFN-γ alone. Conclusions The results of the present study show that IFN-γ and, to a lesser extent TNF-α consistently increase ACE-2 mRNA levels in NHT primary cultures. More interestingly, the combined stimulation (proven to be effective according to the synergic effect registered for CXCL10) produces different responses in terms of ACE-2 mRNA modulation. These results would suggest that elevated levels of pro-inflammatory cytokines could facilitate the entering of the virus in cells by further increasing ACE-2 expression and/or account for the different degree of severity of SARS-COV-2 infection. This hypothesis deserves to be confirmed by further specific studies.

scholarly journals Effects of 14-weeks betaine supplementation on pro-inflammatory cytokines and hematology status in professional youth soccer players during a competition season: a double blind, randomized, placebo-controlled trial

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Hadi Nobari ◽  
Jason M. Cholewa ◽  
Jorge Pérez-Gómez ◽  
Alfonso Castillo-Rodríguez
Keyword(s):  
Inflammatory Cytokines ◽  
Blood Cells ◽  
Well Being ◽  
Soccer Players ◽  
Mean Corpuscular Hemoglobin ◽  
Significant Group ◽  
Youth Soccer ◽  
Tnf Α ◽  
Betaine Supplementation ◽  
Pro Inflammatory Cytokines

Abstract Objective Systemic elevations in pro-inflammatory cytokines are a marker of non-functional over reaching, and betaine has been shown to reduce the secretion of pro-inflammatory cytokines in vitro. The aim of this study was to investigate the effects of betaine supplementation on tumor necrosis factor alpha (TNF-α), interleukins-1 beta (IL-1β), − 6 (IL-6) and the complete blood cell (CBC) count in professional youth soccer players during a competitive season. Methods Twenty-nine soccer players (age, 15.5 ± 0.3 years) were randomly divided into two groups based on playing position: betaine group (BG, n = 14, 2 g/day) or placebo group (PG, n = 15). During the 14-week period, training load was matched and well-being indicators were monitored daily. The aforementioned cytokines and CBC were assessed at pre- (P1), mid- (P2), and post- (P3) season. Results Significant (p < 0.05) group x time interactions were found for TNF-α, IL-1β, and IL-6. These variables were lower in the BG at P2 and P3 compared to P1, while IL-1β was greater in the PG at P3 compared to P1 (p = 0.033). The CBC count analysis showed there was significant group by time interactions for white blood cells (WBC), red blood cells (RBC), hemoglobin (Hb), and mean corpuscular hemoglobin concentration (MCHC). WBC demonstrated increases at P3 compared to P2 in PG (p = 0.034); RBC was less at P3 compared to P1 in BG (p = 0.020); Hb was greater at P2 compared to P1, whilst it was less at P3 compared to P3 for both groups. MCHC was greater at P3 and P2 compared to P1 in BG, whereas MCHC was significantly lower at P3 compared to P2 in the PG (p = 0.003). Conclusion The results confirmed that 14 weeks of betaine supplementation prevented an increase in pro-inflammatory cytokines and WBC counts. It seems that betaine supplementation may be a useful nutritional strategy to regulate the immune response during a fatiguing soccer season.

Montelukast - Its Immunomodulatory and Antiviral Action in COVID-19

2021 ◽  
Vol 8 (21) ◽  
pp. 1731-1732
Author(s):  
Prashant Ramesh Chakkarwar
Keyword(s):  
Tissue Factor ◽  
Inflammatory Cytokines ◽  
Factor Vii ◽  
Clotting Factor ◽  
Activate Factor ◽  
Cytokine Storm ◽  
Oak Ridge ◽  
Montelukast Sodium ◽  
Tnf Α ◽  
Pro Inflammatory Cytokines

Coronavirus disease-19 (COVID-19) is the deadliest pandemic that the whole world is facing today. COVID-19 is different from normal flu by its two lethal manifestations which includes deadly pneumonia which may lead to acute respiratory distress syndrome (ARDS) due to hyper-inflammation of alveolar tissues and pulmonary intravascular coagulopathy (PIC).1,2 It is noteworthy here to mention that both these lethal manifestations of COVID-19 are due to abnormally high levels of pro-inflammatory cytokines like interleukin (IL) - 1β, IL - 6, and tumour necrosis factor (TNF) - α, termed as “cytokine storm.”3,4 There is a certain link between pro-inflammatory cytokines like IL - 1β, IL - 6, and TNF - α and its pro-coagulatory influence on coagulation pathway mediated by tissue factor that binds and activate factor VII, leading to formation of tissue factor – VII a complexes which results in the activation of clotting factor X and IX.4 Recently the researchers in China and some European countries have found raised level of pro-inflammatory cytokines particularly IL - 6 in severe cases of COVID-19. They also found raised D-dimer, fibrinogen levels and prothrombin time in moderate to severe COVID-19 cases.5,6 Both of these lethal manifestations of COVID-19 – ARDS and PIC are linked to raised levels of pro-inflammatory cytokines, particularly, IL - 6. It is not very clear that the pro-inflammatory action of cytokines is mediated through leukotrienes as the biochemical assay for leukotrienes are not widely available but possibility of this probable mechanism cannot be ruled out. Hence, development of any molecule with ability to inhibit pro-inflammatory cytokines, particularly IL-6 may be able to tame the lethal nature of COVID-19, and may ultimately reduce the mortality of this deadly pandemic. Montelukast sodium is such molecule which has capacity to inhibit proinflammatory cytokines such as IL - 1β, IL - 6, and TNF - α.7 Montelukast sodium is leukotriene receptor antagonist that inhibits the cysteinyl leukotriene type-1 receptor. Leukotrienes modulate the production of pro-inflammatory cytokines.8 Its antagonist action on leukotriene receptors can inhibit the production of these pro-inflammatory cytokines. Even recent in silico study by Jacobson at Oak Ridge National Lab, was found that excess bradykinin production may be responsible for pulmonary, cardiac, neurological and nephrological lethal manifestations of COVID-19.9 Crimi et al.10 already found that Montelukast is effective to control bradykinin induced bronchoconstriction. Thus, theoretically, montelukast seems to be best molecule to deal with deadly manifestation of COVID-19 even if we go by cytokine storm hypothesis or bradykinin hypothesis.

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