scholarly journals Pseudane-VII Regulates LPS-Induced Neuroinflammation in Brain Microglia Cells through the Inhibition of iNOS Expression

Molecules ◽  
2018 ◽  
Vol 23 (12) ◽  
pp. 3196 ◽  
Author(s):  
Mi Kim ◽  
Inae Jung ◽  
Ju Na ◽  
Yujeong Lee ◽  
Jaewon Lee ◽  
...  
Keyword(s):  
Neurodegenerative Diseases ◽  
Inflammatory Responses ◽  
Neurological Diseases ◽  
Inos Expression ◽  
Nuclear Factor Kappab ◽  
Nuclear Factor ◽  
Ros Production ◽  
Proinflammatory Mediators ◽  
Cox 2 ◽  
Novel Target

We previously isolated pseudane-VII from the secondary metabolites of Pseudoalteromonas sp. M2 in marine water, and demonstrated its anti-inflammatory efficacy on macrophages. However, the molecular mechanism by which pseudane-VII suppresses neuroinflammation has not yet been elucidated in brain microglia. Microglia is activated by immunological stimulation or brain injury. Activated microglia secrete proinflammatory mediators which damage neurons. Neuroinflammation appears to be associated with certain neurological diseases, including Parkinson’s disease and Alzheimer’s disease. Natural compounds that suppress microglial inflammatory responses could potentially be used to prevent neurodegenerative diseases or slow their progression. In the present study, we found that pseudane-VII suppresses neuroinflammation in lipopolysaccaride (LPS)-stimulated BV-2 microglial cells and brain. Pseudane-VII was shown to inhibit the LPS-stimulated NO, ROS production and the expression of iNOS and COX-2. To identify the signaling pathway targeted by pseudane-VII, we used western blot analysis to assess the LPS-induced phosphorylation state of p38, ERK1/2, JNK1/2, and nuclear factor-kappaB (NF-κB). We found that pseudane-VII attenuated LPS-induced phosphorylation of MAPK and NF-κB. Moreover, administration of pseudane-VII in mice significantly reduced LPS-induced iNOS expression and microglia activation in brain. Taken together, our findings suggest that pseudane-VII may represent a potential novel target for treatment for neurodegenerative diseases.

Requirement of nuclear factor kappaB for the constitutive expression of nitric oxide synthase-2 and cyclooxygenase-2 in rat trophoblasts

1999 ◽  
Vol 112 (18) ◽  
pp. 3147-3155
Author(s):  
N.A. Callejas ◽  
M. Casado ◽  
L. Bosca ◽  
P. Martin-Sanz
Keyword(s):  
Nitric Oxide ◽  
Nitric Oxide Synthase ◽  
Cyclooxygenase 2 ◽  
Nuclear Factor Kappab ◽  
Mrna Levels ◽  
Nuclear Factor ◽  
Cox 2 ◽  
Nf Kappab ◽  
Nitric Oxide Synthase 2 ◽  
Oxide Synthase

Recently isolated trophoblasts express nitric oxide synthase 2 (NOS-2) and cyclooxygenase 2 (COX-2), decreasing the levels of the corresponding mRNAs when the cells were maintained in culture. The sustained expression of COX-2 and NOS-2 in trophoblasts was dependent on the activation of nuclear factor kappaB (NF-kappaB) since proteasome inhibitors and antioxidants that abrogated NF-kappaB activity suppressed the induction of both genes. The time-dependent fall of the mRNA levels of NOS-2 and COX-2 paralleled the inhibition of NF-kappaB, determined by electrophoretic mobility shift assays, and the increase of the IkappaBalpha and IkappaBbeta inhibitory proteins. Isolated trophoblasts synthesized reactive oxygen intermediates (ROI), a process impaired after culturing the cells, and that might be involved in the NF-kappaB activation process. Moreover, treatment of recently isolated cells with ROI scavengers suppressed the expression of COX-2 and NOS-2. Challenge of trophoblasts with interleukin-1beta up-regulated the expression of both proteins, an effect that was potentiated by lipopolysaccharide. These results indicate that the physiological expression of NOS-2 and COX-2 in trophoblasts involves a sustained activation of NF-kappaB which inhibition abrogates the inducibility of both genes.

Mediators released from LPS-challenged lungs induce inflammatory responses in liver vascular endothelial cells and neutrophilic leukocytes

2009 ◽  
Vol 297 (6) ◽  
pp. G1066-G1076 ◽  
Author(s):  
N. Markovic ◽  
L. A. McCaig ◽  
J. Stephen ◽  
S. Mizuguchi ◽  
R. A. W. Veldhuizen ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Inflammatory Response ◽  
Inflammatory Responses ◽  
Vascular Endothelial Cells ◽  
Vascular Endothelial ◽  
Ros Production ◽  
Proinflammatory Mediators ◽  
Primary Mouse ◽  
Mouse Lungs

The systemic inflammatory response plays an important role in the progression of acute lung injury (ALI) to multiple organ dysfunction syndrome (MODS). However, the role of lung-derived inflammatory mediators in induction of the inflammatory response in remote organs is poorly understood. To address the above, we investigated the effects of lung inflammation on induction of inflammatory response(s) in the liver in vitro. Inflammation in mouse lungs was induced by intranasal administration of lipopolysaccharide (LPS; 1 mg/ml) followed by mechanical ventilation using the isolated perfused mouse lung method to obtain and characterize lung perfusate from the pulmonary circulation. LPS administration to mouse lungs resulted in an increased release of inflammation-relevant cytokines and chemokines into the perfusate (Luminex assay) compared with the saline-controls. Subsequently, primary mouse liver vascular endothelial cells (LVEC) or mouse polymorphonuclear leukocytes (PMN) in vitro were stimulated with the perfusate obtained from saline- or LPS-challenged lungs and assessed for various inflammation-relevant end points. The obtained results indicate that stimulation of LVEC with perfusate obtained from LPS-challenged lungs results in 1) reactive oxygen species (ROS) production; 2) activation of NF-κB; and 3) expression of E-selectin, ICAM-1, and VCAM-1 and a subsequent increase in PMN rolling and adhesion to LVEC. In addition, perfusate from LPS-challenged lung induced activation of PMN with respect to increased ROS production and upregulation of cell surface levels of adhesion molecules MAC-1 and VLA-4. Heat-inactivation of the perfusate obtained from LPS-challenged lungs was very effective in suppressing increased proadhesive phenotype (i.e., E-selectin and ICAM-1 expression) in LVEC, whereas targeted inhibition (immunoneutralization) of TNF-α and/or IL-6 in LPS-lung perfusate had no effect. Taken together, these findings indicate that multiple proinflammatory mediators (proteinaceous in nature) released from inflamed lungs act synergistically to induce systemic activation of circulating PMN and promote inflammatory responses in liver vascular endothelial cells.

scholarly journals SUN-254 Angiotensin II Stimulates Microglia Cell Inflammatory Responses

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Jean Paul Moliere Velez ◽  
Dra Yaritza Inostroza-Nieves ◽  
Jose R Romero ◽  
Claudia Arenas ◽  
Diego Capo
Keyword(s):  
Angiotensin Ii ◽  
Neurodegenerative Diseases ◽  
Inflammatory Responses ◽  
Renin Angiotensin System ◽  
Inos Mrna ◽  
No Production ◽  
Ros Production ◽  
Griess Reagent ◽  
Cns Inflammation ◽  
Microglia Cell

Abstract Angiotensin II (AngII) is the principal effector molecule of the renin-angiotensin system (RAS). It’s effects on the cardiovascular and renal system are well-documented. AngII acts mainly via interaction with the AngII type-1 receptor (AT1R). Disordered levels of AngII lead to hypertension and cardiovascular disease. Increasing evidence suggests that AngII may also play a role in the pathophysiology of neurodegenerative diseases through unclear mechanisms. We investigated AngII, AT1R and AT2R levels in a mouse model of neurodegenerative disease, the experimentally induced autoimmune encephalomyelitis (EAE) mouse. In EAE mice, AngII and AT1R gene expression in brain tissue were significantly increased when compared to control mice (3.2 folds ±1.9, p<0.05, n=5; and 2.6 folds ±1.1, p<0.01, n=5 respectively). In addition, iNOS mRNA expression by qRT-PCR was likewise upregulated in EAE mice compared to control (3.4 ± 1.4 folds, p<0.01, n=5). We then studied the effects of AngII in human microglial cells (HMC3) -resident innate immune cells of the central nervous system (CNS). In HMC3 cells, treatment with AngII up-regulated the expression IL-6 (3.9 folds ± 1.2, p<0.01, n=4) and increased IL-6 concentration by 83% (p<0.05, n=4) by ELISA; effects that were blocked by the AT1R antagonist, Losartan. Also, AngII induced TNF-α production, increasing its concentration by 90% (p<0.05, n=4), an increase that was blocked by Losartan. We also quantified Nitric Oxide (NO) production by using Griess Reagent and reactive oxygen species (ROS) production by the MUSE Oxidative Stress assay. In these cells, NO and ROS production were significantly increased by AngII (p<0.05, n=4) and treatment with Losartan reduced their production (p<0.05, n=4). In addition, AngII treatment induced iNOS overexpression (2.5 folds ±0.8, p<0.05, n=4); results that are consistent with increases in the EAE mice. These data suggest that AngII can activate microglia cell inflammatory responses and as such may contribute to the pathophysiology of CNS inflammation and neurodegenerative diseases.

scholarly journals KCHO-1, a Novel Antineuroinflammatory Agent, Inhibits Lipopolysaccharide-Induced Neuroinflammatory Responses through Nrf2-Mediated Heme Oxygenase-1 Expression in Mouse BV2 Microglia Cells

2014 ◽  
Vol 2014 ◽  
pp. 1-11 ◽  
Author(s):  
Dong-Sung Lee ◽  
Wonmin Ko ◽  
Chi-Su Yoon ◽  
Dong-Cheol Kim ◽  
Jinju Yun ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Neurodegenerative Diseases ◽  
Heme Oxygenase ◽  
Nuclear Factor Kappa B ◽  
Heme Oxygenase 1 ◽  
Related Factor ◽  
Nuclear Factor ◽  
Nuclear Factor Kappa ◽  
Bv2 Microglia ◽  
Cox 2

The brain is vulnerable to oxidative stress and inflammation that can occur as a result of aging or neurodegenerative diseases. Our work has sought to identify natural products that regulate heme oxygenase (HO)-1 and to determine their mechanism of action in neurodegenerative diseases. KCHO-1 is a novel herbal therapeutic containing 30% ethanol (EtOH) extracts from nine plants. In this study, we investigated the antineuroinflammatory effects of KCHO-1 in lipopolysaccharide- (LPS-) treated mouse BV2 microglia. KCHO-1 inhibited the protein expression of inducible nitric oxide synthase (iNOS), iNOS-derived nitric oxide (NO), cyclooxygenase- (COX-) 2, and COX-2-derived prostaglandin E2 (PGE2) in LPS-stimulated BV2 microglia. It also reduced tumor necrosis factor-α(TNF-α), interleukin-1β(IL-1β), and IL-6 production. This effect was correlated with the suppression of inhibitor of nuclear factor kappa B-α(IκB-α) phosphorylation and degradation and nuclear factor kappa B (NF-κB) translocation and DNA binding. Additionally, KCHO-1 upregulated HO-1 expression by promoting nuclear translocation of nuclear factor E2-related factor 2 (Nrf2) in mouse BV2 microglia. Tin protoporphyrin (SnPP), an HO activity inhibitor, was used to verify the inhibitory effects of KCHO-1 on proinflammatory mediators and proteins associated with HO-1 expression. Our data suggest that KCHO-1 has therapeutic potential in neurodegenerative diseases caused by neuroinflammation.

BaeR protein acts as an activator of nuclear factor-kappa B and Janus kinase 2 to induce inflammation in murine cell lines

2016 ◽  
Vol 62 (9) ◽  
pp. 753-761
Author(s):  
Seung-Jin Lee ◽  
Biruk Tesfaye Birhanu ◽  
Elias Gebru Awji ◽  
Myung Hee Kim ◽  
Ji-Yong Park ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Nuclear Factor Kappa B ◽  
Inflammatory Responses ◽  
Janus Kinase ◽  
Cytokine Gene Expression ◽  
Raw 264.7 Cells ◽  
Nuclear Factor ◽  
Janus Kinase 2 ◽  
Nuclear Factor Kappa ◽  
Cox 2

BaeR, a response regulator protein, takes part in multidrug efflux, bacterial virulence activity, and other biological functions. Recently, BaeR was shown to induce inflammatory responses by activating the mitogen-activated protein kinases (MAPKs). In this study, we investigated additional pathways used by BaeR to induce an inflammatory response. BaeR protein was purified from Salmonella enterica Paratyphi A and subcloned into a pPosKJ expression vector. RAW 264.7 cells were treated with BaeR, and RNA was extracted by TRIzol reagent for RT-PCR. Cytokine gene expression was analyzed by using the comparative cycle threshold method, while western blotting and ELISA were used to assess protein expression. We confirmed that BaeR activates nuclear factor-kappa B (NF-κB), thereby inducing an inflammatory response and increases the production of interleukins (IL-)1β and IL-6. During this process, the Janus kinase 2 (JAK2)–STAT1 signaling pathway was activated, resulting in an increase in the release of interferons I and II. Additionally, COX-2 was activated and its expression increased with time. In conclusion, BaeR induced an inflammatory response through activation of NF-κB in addition to the MAPKs. Furthermore, activation of the JAK2–STAT1 pathway and COX-2 facilitated the cytokine binding activity, suggesting an additional role for BaeR in the modulation of the immune system of the host and the virulence activity of the pathogen.

scholarly journals Inhibition of Matrix Metalloproteinase with BB-94 Protects against Caerulein-Induced Pancreatitis via Modulating Neutrophil and Macrophage Activation

2020 ◽  
Vol 2020 ◽  
pp. 1-10
Author(s):  
Zengkai Wu ◽  
Tunike Mulatibieke ◽  
Mengya Niu ◽  
Bin Li ◽  
Juanjuan Dai ◽  
...  
Keyword(s):  
Macrophage Activation ◽  
Cell Activation ◽  
Inflammatory Responses ◽  
Macrophage Polarization ◽  
Pancreatic Tissue ◽  
Ros Production ◽  
Proinflammatory Mediators ◽  
Mmp Inhibitor ◽  
M1 Macrophage ◽  
Distant Organ

Background/Objective. Inhibition of matrix metalloproteinases (MMPs), particularly MMP-9, attenuates leukocyte infiltration and pancreatic and distant organ damages in acute pancreatitis (AP). However, it is unclear whether MMPs mediate inflammatory cell activation. In this study, we investigated the effects of inhibition of MMPs on neutrophil and macrophage activation in caerulein-induced pancreatitis. Methods. AP was induced in Balb/C mice by ten hourly intraperitoneal injections of caerulein (100 μg/kg) and LPS (5 mg/kg). The MMP inhibitor, BB-94 (20 mg/kg) was intraperitoneally administered 30 min before AP induction. Pancreatitis was confirmed by histology and serum amylase and lipase. Expression of pancreatic proinflammatory mediators and NF-κB activation were assessed. Bone marrow-derived neutrophils (BMDNs) and macrophages (BMDMs) were isolated. BMDNs were activated by phorbol 12-myristate 13-acetate (PMA, 50 ng/ml) and neutrophil reactive oxygen species (ROS) production was recorded. BMDMs were stimulated with 10 ng/ml IFN-γ and 100 ng/ml LPS to induce M1 macrophage polarization. Results. Pancreatic MMP-9 was markedly upregulated and serum MMP-9 was increased in caerulein-induced pancreatitis. Inhibition of MMP with BB-94 ameliorated pancreatic tissue damage and decreased the expression of proinflammatory cytokines (TNFα and IL-6) or chemokines (CCL2 and CXCL2) and NF-κB activation. Furthermore, using isolated BMDNs and BMDMs, we found that inhibition of MMP with BB-94 markedly decreased neutrophil ROS production, inhibited inflammatory macrophage polarization and NF-κB activation. Conclusions. Our results showed that inhibition of MMP with BB-94 protected against pancreatic inflammatory responses in caerulein-induced pancreatitis via modulating neutrophil and macrophage activation.

Aspirin

1999 ◽  
Vol 56 (12) ◽  
pp. 713-717 ◽  
Author(s):  
Reinhart
Keyword(s):  
Nuclear Factor Kappab ◽  
Nuclear Factor ◽  
Oder Eine ◽  
Cox 2

Acetylsalicylsäure (Aspirin) war das erste synthetisch hergestellte Medikament, das vor 100 Jahren erstmals produziert wurde. Während andere Medikamente alle wieder verschwanden, hat Aspirin einen einmaligen Siegeszug angetreten. Initial wurde es wegen seiner analgetischen, antipyretischen und antiphlogistischen Wirkung gebraucht. Diese basiert auf der Acetylierung der Cyclooxygenase und damit einer Hemmung der Prostaglandinsynthese. In hohen Dosen hemmt Aspirin zusätzlich die intrazelluläre Freisetzung von Nuclear factor-kappaB und damit die Expression von Interleukinen und Tumor-Nekrose-Faktor. Aspirin ist der Prototyp eines nichtsteroidalen Antirheumatikums. In letzter Zeit ist dem Aspirin für diese Wirkung mit den spezifischen Hemmern der Cyclooxygenase Typ 2 (COX-2) Konkurrenz entstanden, deren Stellenwert aber noch nicht endgültig abgeschätzt werden kann. Erst in der 2.Hälfte des Jahrhunderts wurde die Hemmung der Thrombozyten-Aggregation entdeckt. Diese beruht auf einer verminderten Thromboxan A2-Bildung durch die irreversible Schädigung der Cyclooxygenase. Aspirin senkt kardiovaskuläre und zerebrovaskuläre Ereignisse und ist heute das Basismedikament jeder Sekundärprophylaxe bei Gefäßerkrankungen. Auch hier sind potentere Aggregationshemmer mit anderen Wirkmechanismen entwickelt worden wie Ticlopidin, Clopidogrel und Glycoprotein IIb/IIIa-Antagonisten. Alle diese Neuentwicklungen müssen sich erst noch bewähren und sind um ein Mehrfaches teurer als Aspirin, das weiterhin erste Wahl bleibt. Immer wieder werden neue Wirkungen von Aspirin beschrieben, wie z.B. eine Verbesserung der Endothelfunktion oder eine deutliche Verminderung des Risikos für Kolonkarzinome. Aspirin dürfte weit ins nächste Jahrhundert hinein weiterleben und scheint für eine Vielzahl von Krankheiten noch lange nicht ausgedient zu haben.

Taraxacum officinale Wigg. Attenuates Inflammatory Responses in Murine Microglia through the Nrf2/HO-1 and NF-κB Signaling Pathways

2020 ◽  
Vol 48 (02) ◽  
pp. 445-462
Author(s):  
Linsha Dong ◽  
Zhuoma Dongzhi ◽  
Yonglong Jin ◽  
Youn-Chul Kim ◽  
Dong-Sung Lee ◽  
...  
Keyword(s):  
Nuclear Translocation ◽  
Inflammatory Responses ◽  
Taraxacum Officinale ◽  
Related Factor ◽  
Nuclear Factor ◽  
Proinflammatory Mediators ◽  
Bv2 Cells ◽  
Murine Microglia ◽  
Anti Inflammatory ◽  
Ethanol Extracts

As a long-established medicinal and edible homologous plant, Taraxacum officinale Wigg. is widely distributed in Asia, Europe, and other parts of the world. T. officinale is reported to exert a variety of biological and pharmacological activities, including anticancer, hepatoprotective, and anti-obesity effects. In this study, we evaluated the anti-inflammatory effects of ethanol extracts of T. officinale (A-TOW) by examining the suppression of proinflammatory mediators in LPS-stimulated BV2 and mouse hippocampus. Furthermore, A-TOW also inhibited the nuclear translocation of nuclear factor [Formula: see text]B p65 caused by stimulation with LPS. In addition, A-TOW regulates heme oxygenase (HO)-1 expression through the nuclear translocation of nuclear factor E2-related factor 2 (Nrf2) in BV2 cells. The effects of A-TOW on the over-expression of proinflammatory mediators were partially reversed by transfection of the cells with HO-1 siRNA. These findings suggest that the potent anti-inflammatory activity of T. officinale, possibly through the regulation of Nrf2/HO-1 and NF-[Formula: see text]B signaling pathway.

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