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.

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.

Mitigation of IL-1β, IL-6, TNF-α, and markers of apoptosis by ursolic acid against cisplatin-induced oxidative stress and nephrotoxicity in rats

2021 ◽  
Vol 40 (12_suppl) ◽  
pp. S397-S405
Author(s):  
Pankaj Tripathi ◽  
Saeed Alshahrani
Keyword(s):  
Oxidative Stress ◽  
Antioxidant Activity ◽  
Uric Acid ◽  
Inflammatory Cytokines ◽  
Caspase 3 ◽  
Caspase 9 ◽  
Histological Damage ◽  
Tnf Α ◽  
Mda Content ◽  
Pro Inflammatory Cytokines

Background: Ursolic acid (UA) is a natural pentacyclic triterpenoid that is known for its benefits under several pathological conditions. Cisplatin (CP) is among the most preferred chemotherapeutic agents; however, its nephrotoxicity limits its clinical utility. Purpose: This study was aimed to determine the role of UA in the reduction of CP-induced nephrotoxicity and mitigation of pro-inflammatory cytokines and apoptosis in a rat model. Methodology: Male Wistar rats were randomized into vehicle control, CP (7.5 mg/kg), UA 10 mg/kg, and CP with UA 5 and 10 mg/kg groups. Kidney and blood samples were collected for assessment of renal function, measurement of pro-inflammatory cytokines, apoptosis markers, antioxidant activity, and tissue histology. Results: CP significantly increased the levels of serum Cr, BUN, and uric acid; it also induced histological damage reflecting the pathophysiology observed during nephrotoxicity. CP has also shown its pro-oxidant activity in kidney tissue because CP decreased the levels of GSH, SOD, and CAT; it increased the lipid peroxidation as measured by MDA content. In addition, CP significantly upregulated the activity of pro-inflammatory cytokines and expression of apoptotic markers, that is, there were increased levels of IL-1β, IL-6, TNF-α, caspase-3, and caspase-9. Two weeks of continuous treatment of UA showed significant recovery against CP-induced nephrotoxicity; UA decreased the levels of Cr, BUN, and uric acid and ameliorated histological damage. UA also downregulated the activities of IL-1β, IL-6, and TNF-α as well as expression of caspase-3 and caspase-9. Furthermore, CP-induced oxidative stress that was antagonized by UA—the levels of GSH, SOD, and CAT were significantly increased while MDA content was decreased. Conclusions: UA has a protective effect against CP-induced nephrotoxicity, which may be due to its antioxidant activity and mitigation of ILβ-1, ILβ-6, TNF-α, and markers of apoptosis.

scholarly journals The Influence of Sevelamer Hydrochloride and Calcium Carbonate on Markers of Inflammation and Oxidative Stress in Hemodialysis at Six Months of Follow-Up

2021 ◽  
Vol 8 ◽  
Author(s):  
Elodia Nataly Díaz-De la Cruz ◽  
José Ignacio Cerrillos-Gutiérrez ◽  
Andrés García-Sánchez ◽  
Carlos Gerardo Prado-Nevárez ◽  
Jorge Andrade-Sierra ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Calcium Carbonate ◽  
Inflammatory Cytokines ◽  
C Reactive Protein ◽  
Reactive Protein ◽  
Sevelamer Hydrochloride ◽  
Tnf Α ◽  
Compensatory Effect ◽  
Pro Inflammatory Cytokines

Patients with end-stage renal disease (ESRD) present alterations in mineral and bone metabolism. Hyperphosphatemia in ESRD is considered an independent risk factor for cardiovascular disease (CVD), increasing morbidity, and mortality. Sevelamer hydrochloride is a calcium-free, non-absorbable phosphate-chelating polymer. Calcium carbonate chelator is helpful in controlling serum phosphate levels. There is insufficient information on the influence of sevelamer hydrochloride and calcium carbonate on the behavior of oxidative stress (OS) markers and inflammation in patients on hemodialysis (HD). A randomized open clinical trial was carried out on patients to evaluate sevelamer hydrochloride and calcium carbonate influence at 6 months of study follow-up. Levels of oxidants (LPO, NO, and 8-isoprostanes), antioxidants (SOD and TAC), oxidative DNA damage (8-OHdG and hOGG1), pro-inflammatory cytokines (IL-6 and TNF-α), and inflammation markers (ferritin and C-reactive protein) were measured with colorimetric and ELISA methods. We found a significant increase in oxidants LPO and NO, and antioxidants SOD and TAC, and downregulation of IL-6 and TNF-α. Ferritin decrease at 6 months follow-up in the sevelamer hydrochloride group. Increase in C-reactive protein was found in the group of patients treated with calcium carbonate. In conclusion, we found an oxidative state imbalance with increase in LPO and NO oxidants. The activity of the antioxidant enzymes (SOD and TAC) was also found to increase, suggesting a compensatory effect in the face of increase in oxidants. The same phenomenon was observed with increase in the oxidative damage marker to DNA and the increase in the DNA repair enzyme, suggesting a compensatory effect. Pro-inflammatory cytokines were predominantly downregulated by TNF-α in the group that ingested sevelamer hydrochloride in the final determination at 6 months of follow-up. Serum ferritin levels decreased significantly at the end of follow-up in patients on HD in the sevelamer hydrochloride group. The management of hyperphosphatemia with sevelamer hydrochloride appears to have obvious anti-inflammatory and antioxidant benefits.

scholarly journals Dexmedetomidine Alleviates Microglia-Induced Spinal Inflammation and Hyperalgesia in Neonatal Rats by Systemic Lipopolysaccharide Exposure

2021 ◽  
Vol 15 ◽  
Author(s):  
Wen Wen ◽  
Xingrui Gong ◽  
Hoiyin Cheung ◽  
Yanyan Yang ◽  
Meihua Cai ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Inflammatory Cytokines ◽  
Bacterial Infections ◽  
Microglial Activation ◽  
Neuroprotective Effect ◽  
Mechanical Hyperalgesia ◽  
Neonatal Rats ◽  
Microglial Polarization ◽  
Spinal Inflammation ◽  
Pro Inflammatory Cytokines

Noxious stimulus and painful experience in early life can induce cognitive deficits and abnormal pain sensitivity. As a major component of the outer membrane of gram-negative bacteria, lipopolysaccharide (LPS) injection mimics clinical symptoms of bacterial infections. Spinal microglial activation and the production of pro-inflammatory cytokines have been implicated in the pathogenesis of LPS-induced hyperalgesia in neonatal rats. Dexmedetomidine (DEX) possesses potent anti-neuroinflammatory and neuroprotective properties through the inhibition of microglial activation and microglial polarization toward pro-inflammatory (M1) phenotype and has been widely used in pediatric clinical practice. However, little is known about the effects of DEX on LPS-induced spinal inflammation and hyperalgesia in neonates. Here, we investigated whether systemic LPS exposure has persistent effects on spinal inflammation and hyperalgesia in neonatal rats and explored the protective role of DEX in adverse effects caused by LPS injection. Systemic LPS injections induced acute mechanical hyperalgesia, increased levels of pro-inflammatory cytokines in serum, and short-term increased expressions of pro-inflammatory cytokines and M1 microglial markers in the spinal cord of neonatal rats. Pretreatment with DEX significantly decreased inflammation and alleviated mechanical hyperalgesia induced by LPS. The inhibition of M1 microglial polarization and microglial pro-inflammatory cytokines expression in the spinal cord may implicate its neuroprotective effect, which highlights a new therapeutic target in the treatment of infection-induced hyperalgesia in neonates and preterm infants.

CNS inflammation and neurodegeneration: sequelae of peripheral inoculation with spinal cord tissue in rat

2020 ◽  
Vol 132 (3) ◽  
pp. 933-944 ◽  
Author(s):  
Lonnie Schneider ◽  
Ethan Reichert ◽  
Jenna Faulkner ◽  
Brielle Reichert ◽  
Joshua Sonnen ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Morris Water Maze ◽  
Inflammatory Cytokines ◽  
Water Maze ◽  
Spinal Cord Tissue ◽  
Tnf Α ◽  
Β Amyloid ◽  
Brain And Spinal Cord ◽  
The Brain ◽  
Pro Inflammatory Cytokines

OBJECTIVERecent research demonstrates that victims of spinal cord injury (SCI) are at increased risk for dementia and that encephalitis can occur as a consequence of isolated SCI. We theorize that autoimmunity to the central nervous system (CNS) could explain these phenomena and undertook this study to determine whether peripheral inoculation with spinal cord homogenate on 1 or 2 occasions is associated with CNS-directed autoimmunity and neurodegeneration in a rat model.METHODSRats were subcutaneously inoculated with saline or 75 mg of allogeneic spinal cord tissue on 1 or 2 occasions. Animals underwent Morris Water Maze testing, and serial serum samples were collected. Animals were sacrificed 8 weeks following the first inoculation. Autoantibody titers to myelin antigens MAG and GM1 were measured in serum. Immunohistochemistry was used to identify autoantibodies targeting NeuN-labeled neurons and CC1-labeled oligodendrocytes. Quantitative real-time polymerase chain reaction (qPCR) and western blotting were performed for pro-inflammatory cytokines TNF-α, IL-1β, and IL-6 and the cell death marker caspase 3 as well as the neurodegenerative proteins tau and β-amyloid in both brain and spinal cord. Fluoro-Jade B was used to stain degenerating neurons, facilitating counting.RESULTSAnimals inoculated with spinal cord homogenate exhibited increased titers of autoantibodies to MAG and GM1 and autoantibodies binding to neurons and oligodendrocytes. Double-inoculated animals demonstrated a significant increase in the expression of pro-inflammatory cytokines in the brain (TNF-α, p = 0.016; IL-6, p = 0.009) as well as the spinal cord (TNF-α, p = 0.024; IL-6, p = 0.002). The number of degenerating neurons was significantly increased in the brain and spinal cord of inoculated animals (p < 0.0001 and p = 0.028, respectively). Elevated expression of tau and β-amyloid was seen in brain of double-inoculated animals (p = 0.003 and p = 0.009, respectively). Inflammatory marker expression in the brain was positively correlated with anti-myelin autoimmune antibody titers and with tau expression in the brain. Inoculated animals showed impaired memory function in Morris Water Maze testing (p = 0.043).CONCLUSIONSThe results of these experiments demonstrate that peripheral exposure to spinal cord antigens is associated with CNS-directed autoimmunity and inflammation in the brain and spinal cord as well as degeneration of CNS cells, memory impairment, and production of neurodegenerative proteins particularly when this exposure is repeated. These data support CNS autoimmunity as a candidate mechanism for the dementia that can follow SCI and perhaps other posttraumatic dementias such as chronic traumatic encephalopathy.

scholarly journals Beneficial effects of combined therapy with lacidipine and candesartan in obese hypertensive patients

2018 ◽  
Vol 56 (4) ◽  
pp. 257-264
Author(s):  
Tatiana Ashcheulova ◽  
Nina Gerasimchuk ◽  
Olga Kovalyova ◽  
Oleksii Honchar
Keyword(s):  
Oxidative Stress ◽  
Endothelial Function ◽  
Antihypertensive Therapy ◽  
Inflammatory Cytokines ◽  
Overweight And Obesity ◽  
Oxidative Stress Marker ◽  
Hypertensive Patients ◽  
Tnf Α ◽  
And Oxidative Stress ◽  
Pro Inflammatory Cytokines

Abstract Introduction. Obesity is becoming one of the leading risk factors of coronary heart disease, hypertension, cerebrovascular disease. Despite the presence of a large number of antihypertensive agents and scientific substantiation of antihypertensive treatment principles it would be wrong to assume that the problem is completely solved. Development of endothelial dysfunction is one of the key pathogenic mechanisms in hypertension. This process is proven to have contributed by immune inflammation activation which is mediated by pro-inflammatory cytokines and oxidative stress. Aims. To investigate the additional benefits of the combined antihypertensive therapy with lacidipine and candesartan on the basis of studying their antioxidant properties, impact on endothelial function and pro-inflammatory cytokines activity in hypertensive patients with overweight and obesity. Methods. A combination of a calcium channel blocker and angiotensin receptor blocker (lacidipine 2 mg, 4 mg, and candesartan 4mg, 8mg, 16mg) was prescribed to 30 patients with essential hypertension of grades 1-3, 30 to 65 years old (mean age - 54.7 ± 5.8 years), who previously have not been receiving regular antihypertensive therapy. Results. During the course of combined antihypertensive therapy with lacidipine and candesartan, a significant reduction in i-NOS activity, TNF-α to its type I soluble receptor ratio (TNF- α/sTNF-αRI), and oxidative stress marker - 8-iso-PgF2α has been observed. Activity of e-NOS, levels of SOD and catalase, in contrast, have increased by the end of observation period. Conclusion. The improvement of endothelial function due to lower level of oxidative stress and a significant decrease of immune activation has been observed in hypertensive patients with overweight and obesity under the influence of combined antihypertensive therapy with lacidipine and candesartan.

MO596HYPERPHOSPHATEMIA INDUCES ENDOTHELIN-1 SYNTHESIS AND INFLAMMATION IN LUNG FIBROBLASTS

2021 ◽  
Vol 36 (Supplement_1) ◽  
Author(s):  
Ana Asenjo-Bueno ◽  
Elena Alcalde-Estevez ◽  
Gemma Olmos ◽  
Diego Rodríguez-Puyol ◽  
Maria Piedad Ruiz-Torres ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Lung Function ◽  
Real Time ◽  
Chronic Diseases ◽  
Inflammatory Cytokines ◽  
Real Time Pcr ◽  
Lung Fibroblasts ◽  
Ros Production ◽  
Tnf Α ◽  
Pro Inflammatory Cytokines

Abstract Background and Aims Hyperphosphatemia is an aging-related condition associated to chronic diseases such as chronic kidney disease (CKD). In both cases, aging and CKD, it has been described a decline lung function, however, relationship between high serum levels of phosphate and lung damage has not been described yet. The aim of this work was to evaluate if phosphate could induce inflammation in lung, studying the mechanisms implied. Method In vitro studies were performed on a cell line from human lung fibroblasts (Wi-38) which were treated with a phosphate donor termed β-glycerophosphate (BGP, 10 mM) and also with endothelin 1 (ET-1, 10 nM) at different times. To assess inflammation, the expression of several cytokines such as TNF-α,IL-1β, IL-6 and MCP-1 were measured by real time PCR. mRNA expressions of prepro-ET-1 and endothelin-converting enzyme-1 (ECE-1) were also analyzed by real time PCR. Reactive oxygen species (ROS) production was evaluated by confocal microscopy in live cells using the fluorogenic probe CellROX as oxidative stress reagent. Results Treatment with BGP induced a significant rise of the pro-inflammatory cytokines expression, TNF-α, IL-1β, IL-6 and MCP-1, on lung fibroblasts. Moreover, BGP was able to regulate ET-1 system, as we found a significant increase of mRNA expressions not only of prepro-ET-1 but also of ECE-1, reaching a peak around 2 and 6 hours, respectively. Later, it was checked whether ET-1 could induce inflammation itself in lung fibroblasts. Cells incubated with ET-1 show similar results as BGP, increasing expressions of all cytokines, TNF-α, IL-1β, IL-6 and MCP-1.ET-1 response was earlier than BGP, around at 2 hours with ET-1 instead of at 8 hours with BGP. In order to elucidate a possible mechanism, ROS production was assessed after BGP treatment. BGP induced ROS production at 15 min in lung fibroblasts. Conclusion BGP induces the synthesis of pro-inflammatory cytokines as well as the system of synthesis of ET-1, besides to rise ROS production.ET-1 itself also increases pro-inflammatory cytokines expression. ET-1 could contribute to the inflammation observed in lung fibroblast after BGP treatment. We propose oxidative stress as a potential mechanism implied, as it is well known that ROS can mediate in inflammation and in the ET system. However, more studies are necessary to confirm this role. All in all, these results relate hyperphosphatemia with a higher inflammation in lung fibroblasts which could decline lung function in chronic diseases associated to aging as CKD.

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