Suppression of LPS-induced inflammatory responses by inflexanin B in BV2 microglial cells

2013 ◽  
Vol 91 (2) ◽  
pp. 141-148 ◽  
Author(s):  
Ji-Youn Lim ◽  
Donggeun Sul ◽  
Bang Yeon Hwang ◽  
Kwang Woo Hwang ◽  
Ki-Yeol Yoo ◽  
...  
Keyword(s):  
Inflammatory Mediators ◽  
Nuclear Translocation ◽  
Inflammatory Responses ◽  
Mitogen Activated Protein Kinase ◽  
Bv2 Cells ◽  
Mitogen Activated Protein ◽  
Physiological Homeostasis ◽  
The Central Nervous System ◽  
Factor Α ◽  
Bv2 Microglial Cells

Microglia are a type of resident macrophage that functions as an inflammation modulator in the central nervous system. Over-activation of microglia by a range of stimuli disrupts the physiological homeostasis of the brain, and induces inflammatory response and degenerative processes, such as those implicated in neurodegenerative diseases, including Alzheimer's disease and Parkinson's disease. Therefore, we investigated the possible anti-inflammatory mechanisms of inflexanin B in murine microglial BV2 cells. Lipopolysaccharide (LPS) activated BV2 cells and induced the production of pro-inflammatory mediators such as nitric oxide (NO), prostaglandin E2 (PGE2), and cytokines (interleukins-1β and -6, and tumour necrosis factor α). The LPS-induced production of pro-inflammatory mediators was associated with the enhancement of nuclear factor-kappaB (NF-κB) nuclear translocation and the activation of mitogen-activated protein kinase (MAPK) including ERK1/2 and JNK. Conversely, pretreatment of cells with inflexanin B (10 and 20 μg/mL) significantly reduced the production of pro-inflammatory mediators. This was accompanied with the reduced nuclear translocation of NF-κB and reduced activation of MAPKs. These results suggest that inflexanin B attenuated the LPS-induced inflammatory process by inhibiting the activation of NF-κB and MAPKs.

scholarly journals A Novel 1,8-Naphthyridine-2-Carboxamide Derivative Attenuates Inflammatory Responses and Cell Migration in LPS-Treated BV2 Cells via the Suppression of ROS Generation and TLR4/Myd88/NF-κB Signaling Pathway

2021 ◽  
Vol 22 (5) ◽  
pp. 2527
Author(s):  
Phuong Linh Nguyen ◽  
Bich Phuong Bui ◽  
Heesoon Lee ◽  
Jungsook Cho
Keyword(s):  
Cell Migration ◽  
Signaling Pathway ◽  
Inflammatory Mediators ◽  
Nuclear Translocation ◽  
Inflammatory Responses ◽  
Specific Inhibitor ◽  
Nuclear Factor Κb ◽  
Ros Generation ◽  
Bv2 Cells ◽  
Factor Α

Novel 1,8-naphthyridine-2-carboxamide derivatives with various substituents (HSR2101-HSR2113) were synthesized and evaluated for their effects on the production of pro-inflammatory mediators and cell migration in lipopolysaccharide (LPS)-treated BV2 microglial cells. Among the tested compounds, HSR2104 exhibited the most potent inhibitory effects on the LPS-stimulated production of inflammatory mediators, including nitric oxide (NO), tumor necrosis factor-α, and interleukin-6. Therefore, this compound was chosen for further investigation. We found that HSR2104 attenuated levels of inducible NO synthase and cyclooxygenase 2 in LPS-treated BV2 cells. In addition, it markedly suppressed LPS-induced cell migration as well as the generation of intracellular reactive oxygen species (ROS). Moreover, HSR2104 abated the LPS-triggered nuclear translocation of nuclear factor-κB (NF-κB) through inhibition of inhibitor kappa Bα phosphorylation. Furthermore, it reduced the expressions of Toll-like receptor 4 (TLR4) and myeloid differentiation factor 88 (MyD88) in LPS-treated BV2 cells. Similar results were observed with TAK242, a specific inhibitor of TLR4, suggesting that TLR4 is an upstream regulator of NF-κB signaling in BV2 cells. Collectively, our findings demonstrate that HSR2104 exhibits anti-inflammatory and anti-migratory activities in LPS-treated BV2 cells via the suppression of ROS and TLR4/MyD88/NF-κB signaling pathway. Based on our observations, HSR2104 may have a beneficial impact on inflammatory responses and microglial cell migration involved in the pathogenesis of various neurodegenerative disorders.

scholarly journals Carbon dioxide inhibits COVID-19-type proinflammatory responses through extracellular signal-regulated kinases 1 and 2, novel carbon dioxide sensors

2021 ◽  
Author(s):  
Hanna Galganska ◽  
Wieslawa Jarmuszkiewicz ◽  
Lukasz Galganski
Keyword(s):  
Carbon Dioxide ◽  
Endothelial Cells ◽  
Inflammatory Responses ◽  
Mitogen Activated Protein Kinase ◽  
Extracellular Signal ◽  
Mapk Signalling ◽  
Mitogen Activated Protein ◽  
Proinflammatory Responses ◽  
Factor Α ◽  
Preclinical And Clinical Studies

AbstractMitogen-activated protein kinase (MAPK) signalling pathways are crucial for developmental processes, oncogenesis, and inflammation, including the production of proinflammatory cytokines caused by reactive oxygen species and upon severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. There are no drugs that can effectively prevent excessive inflammatory responses in endothelial cells in the lungs, heart, brain, and kidneys, which are considered the main causes of severe coronavirus disease 2019 (COVID-19). In this work, we demonstrate that human MAPKs, i.e. extracellular signal-regulated kinases 1 and 2 (ERK1/2), are CO2 sensors and CO2 is an efficient anti-inflammatory compound that exerts its effects through inactivating ERK1/2 in cultured endothelial cells when the CO2 concentration is elevated. CO2 is a potent inhibitor of cellular proinflammatory responses caused by H2O2 or the receptor-binding domain (RBD) of the spike protein of SARS-CoV-2. ERK1/2 activated by the combined action of RBD and cytokines crucial for the development of severe COVID-19, i.e. interferon-gamma (IFNγ) and tumour necrosis factor-α (TNFα), are more effectively inactivated by CO2 than by dexamethasone or acetylsalicylic acid in human bronchial epithelial cells. Previously, many preclinical and clinical studies showed that the transient application of 5–8% CO2 is safe and effective in the treatment of many diseases. Therefore, our research indicates that CO2 may be used for the treatment of COVID-19 as well as the modification of hundreds of cellular pathways.

Glycyrrhizin, the main active compound in liquorice, attenuates pro-inflammatory responses by interfering with membrane-dependent receptor signalling

2009 ◽  
Vol 421 (3) ◽  
pp. 473-482 ◽  
Author(s):  
Bärbel Schröfelbauer ◽  
Johanna Raffetseder ◽  
Maria Hauner ◽  
Andrea Wolkerstorfer ◽  
Wolfgang Ernst ◽  
...  
Keyword(s):  
Active Compound ◽  
Inflammatory Responses ◽  
Nuclear Factor Κb ◽  
Mitogen Activated Protein Kinase ◽  
Raw 264.7 Cells ◽  
Cpg Dna ◽  
Cellular Attachment ◽  
Mitogen Activated Protein ◽  
Anti Inflammatory ◽  
Factor Α

The triterpene glycoside glycyrrhizin is the main active compound in liquorice. It is used as a herbal medicine owing to its anticancer, antiviral and anti-inflammatory properties. Its mode of action, however, remains widely unknown. In the present study, we aimed to elucidate the molecular mechanism of glycyrrhizin in attenuating inflammatory responses in macrophages. Using microarray analysis, we found that glycyrrhizin caused a broad block in the induction of pro-inflammatory mediators induced by the TLR (Toll-like receptor) 9 agonist CpG-DNA in RAW 264.7 cells. Furthermore, we found that glycyrrhizin also strongly attenuated inflammatory responses induced by TLR3 and TLR4 ligands. The inhibition was accompanied by decreased activation not only of the NF-κB (nuclear factor κB) pathway but also of the parallel MAPK (mitogen-activated protein kinase) signalling cascade upon stimulation with TLR9 and TLR4 agonists. Further analysis of upstream events revealed that glycyrrhizin treatment decreased cellular attachment and/or uptake of CpG-DNA and strongly impaired TLR4 internalization. Moreover, we found that the anti-inflammatory effects were specific for membrane-dependent receptor-mediated stimuli, as glycyrrhizin was ineffective in blocking Tnfa (tumour necrosis factor α gene) induction upon stimulation with PMA, a receptor- and membrane-independent stimulus. These observations suggest that the broad anti-inflammatory activity of glycyrrhizin is mediated by the interaction with the lipid bilayer, thereby attenuating receptor-mediated signalling.

scholarly journals Suppression of LPS-Induced Inflammation and Cell Migration by Azelastine through Inhibition of JNK/NF-κB Pathway in BV2 Microglial Cells

2021 ◽  
Vol 22 (16) ◽  
pp. 9061
Author(s):  
Phuong Linh Nguyen ◽  
Bich Phuong Bui ◽  
Men Thi Hoai Duong ◽  
Kyeong Lee ◽  
Hee-Chul Ahn ◽  
...  
Keyword(s):  
Cell Migration ◽  
Inflammatory Mediators ◽  
Nuclear Translocation ◽  
Drug Repurposing ◽  
Microglial Cells ◽  
Potential Candidate ◽  
Jnk Pathway ◽  
Bv2 Cells ◽  
Parkinson’S Diseases ◽  
Bv2 Microglial Cells

The c-Jun N-terminal kinases (JNKs) are implicated in many neuropathological conditions, including neurodegenerative diseases. To explore potential JNK3 inhibitors from the U.S. Food and Drug Administration-approved drug library, we performed structure-based virtual screening and identified azelastine (Aze) as one of the candidates. NMR spectroscopy indicated its direct binding to the ATP-binding site of JNK3, validating our observations. Although the antihistamine effect of Aze is well documented, the involvement of the JNK pathway in its action remains to be elucidated. This study investigated the effects of Aze on lipopolysaccharide (LPS)-induced JNK phosphorylation, pro-inflammatory mediators, and cell migration in BV2 microglial cells. Aze was found to inhibit the LPS-induced phosphorylation of JNK and c-Jun. It also inhibited the LPS-induced production of pro-inflammatory mediators, including interleukin-6, tumor necrosis factor-α, and nitric oxide. Wound healing and transwell migration assays indicated that Aze attenuated LPS-induced BV2 cell migration. Furthermore, Aze inhibited LPS-induced IκB phosphorylation, thereby suppressing nuclear translocation of NF-κB. Collectively, our data demonstrate that Aze exerts anti-inflammatory and anti-migratory effects through inhibition of the JNK/NF-κB pathway in BV2 cells. Based on our findings, Aze may be a potential candidate for drug repurposing to mitigate neuroinflammation in various neurodegenerative disorders, including Alzheimer’s and Parkinson’s diseases.

Chloroquine attenuates lipopolysaccharide-induced inflammatory responses through upregulation of USP25

2017 ◽  
Vol 95 (5) ◽  
pp. 481-491 ◽  
Author(s):  
Changyu Ding ◽  
Fangfang Li ◽  
Yupeng Long ◽  
Jiang Zheng
Keyword(s):  
Macrophage Activation ◽  
Nuclear Translocation ◽  
Inflammatory Responses ◽  
Ubiquitin Proteasome System ◽  
Mitogen Activated Protein Kinase ◽  
Dependent Manner ◽  
Activation Of Transcription ◽  
Tnf Α ◽  
Mitogen Activated Protein ◽  
Ubiquitin Proteasome

Lipopolysaccharide (LPS) is a key pathogenic factor in sepsis, and its recognition by toll-like receptor 4 (TLR4) can activate two district signaling pathways, leading to activation of transcription factors including NF-κB and interferon regulatory factor 3 (IRF3). Chloroquine (CQ) has been shown to affect LPS–TLR4 colocalization and inhibit both MyD88-dependent and TRAM/TRIF-dependent pathways, though the mechanism involved is still poorly understood. Here, we found that the ubiquitin–proteasome system might be involved in this process. CQ increased USP25, a deubiquitinating enzyme, as well as mRNA and protein expression in a dose-dependent manner, which might to some degree be involved in CQ attenuation of LPS-induced macrophage activation. Overexpression of USP25 decreased LPS-induced inflammatory cytokines like TNF-α, IL-6, and IFN-β, while specific siRNA-mediated USP25 silencing increased TNF-α, IL-6, and IFN-β production and secretion. In addition, USP25 deletion strengthened mitogen-activated protein kinase (MAPKs) phosphorylation and IκB degradation. Moreover, USP25 interference increased NF-κB and IRF3 nuclear translocation. Taken together, our data demonstrated a new possible regulator of LPS-induced macrophage activation mediated by CQ, through upregulation of USP25.

scholarly journals Anti-Inflammatory and Anti-Migratory Activities of Isoquinoline-1-Carboxamide Derivatives in LPS-Treated BV2 Microglial Cells via Inhibition of MAPKs/NF-κB Pathway

2020 ◽  
Vol 21 (7) ◽  
pp. 2319 ◽  
Author(s):  
Ha Thi Thu Do ◽  
Bich Phuong Bui ◽  
Seongrak Sim ◽  
Jae-Kyung Jung ◽  
Heesoon Lee ◽  
...  
Keyword(s):  
Cell Migration ◽  
Inflammatory Mediators ◽  
Nuclear Translocation ◽  
Microglial Cells ◽  
Necrosis Factor Alpha ◽  
Mitogen Activated Protein ◽  
Upstream Kinase ◽  
Anti Inflammatory ◽  
Mapk Inhibitors ◽  
Bv2 Microglial Cells

Eleven novel isoquinoline-1-carboxamides (HSR1101~1111) were synthesized and evaluated for their effects on lipopolysaccharide (LPS)-induced production of pro-inflammatory mediators and cell migration in BV2 microglial cells. Three compounds (HSR1101~1103) exhibited the most potent suppression of LPS-induced pro-inflammatory mediators, including interleukin (IL)-6, tumor necrosis factor-alpha, and nitric oxide (NO), without significant cytotoxicity. Among them, only N-(2-hydroxyphenyl) isoquinoline-1-carboxamide (HSR1101) was found to reverse LPS-suppressed anti-inflammatory cytokine IL-10, so it was selected for further characterization. HSR1101 attenuated LPS-induced expression of inducible NO synthase and cyclooxygenase-2. Particularly, HSR1101 abated LPS-induced nuclear translocation of NF-κB through inhibition of IκB phosphorylation. Furthermore, HSR1101 inhibited LPS-induced cell migration and phosphorylation of mitogen-activated protein kinases (MAPKs) including extracellular signal-regulated kinase 1/2, c-Jun N-terminal kinase, and p38 MAPK. The specific MAPK inhibitors, U0126, SP600125, and SB203580, suppressed LPS-stimulated pro-inflammatory mediators, cell migration, and NF-κB nuclear translocation, indicating that MAPKs may be the upstream kinase of NF-κB signaling. Collectively, these results demonstrate that HSR1101 is a potent and promising compound suppressing LPS-induced inflammation and cell migration in BV2 microglial cells, and that inhibition of the MAPKs/NF-κB pathway mediates its anti-inflammatory and anti-migratory effects. Based on our findings, HSR1101 may have beneficial impacts on various neurodegenerative disorders associated with neuroinflammation and microglial activation.

scholarly journals Inflammatory Mediators and Stroke: New Opportunities for Novel Therapeutics

1999 ◽  
Vol 19 (8) ◽  
pp. 819-834 ◽  
Author(s):  
Frank C. Barone ◽  
Giora Z. Feuerstein
Keyword(s):  
Brain Injury ◽  
Inflammatory Mediators ◽  
Tissue Injury ◽  
Interleukin 1 ◽  
Mitogen Activated Protein Kinase ◽  
Tissue Loss ◽  
Cytokines And Chemokines ◽  
Basic Work ◽  
Mitogen Activated Protein ◽  
Factor Α

Contrary to previous dogmas, it is now well established that brain cells can produce cytokines and chemokines, and can express adhesion molecules that enable an in situ inflammatory reaction. The accumulation of neutrophils early after brain injury is believed to contribute to the degree of brain tissue loss. Support for this hypothesis has been drawn from many studies where neutrophil-depletion blockade of endothelial-leukocyte interactions has been achieved by various techniques. The inflammation reaction is an attractive pharmacologic opportunity, considering its rapid initiation and progression over many hours after stroke and its contribution to evolution of tissue injury. While the expression of inflammatory cytokines that may contribute to ischemic injury has been repeatedly demonstrated, cytokines may also provide “neuroprotection” in certain conditions by promoting growth, repair, and ultimately, enhanced functional recovery. Significant additional basic work is required to understand the dynamic, complex, and time-dependent destructive and protective processes associated with inflammation mediators produced after brain injury. The realization that brain ischemia and trauma elicit robust inflammation in the brain provides fertile ground for discovery of novel therapeutic agents for stroke and neurotrauma. Inhibition of the mitogen-activated protein kinase (MAPK) cascade via cytokine suppressive anti-inflammatory drugs, which block p38 MAPK and hence the production of interleukin-1 and tumor necrosis factor-α, are most promising new opportunities. However, spatial and temporal considerations need to be exercised to elucidate the best opportunities for selective inhibitors for specific inflammatory mediators.

scholarly journals Sec22b regulates inflammatory responses by controlling the nuclear translocation of NF-κB

2020 ◽  
Author(s):  
Guillermo Arango Duque ◽  
Renaud Dion ◽  
Aymeric Fabié ◽  
Julien Descoteaux ◽  
Simona Stäger ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Dendritic Cells ◽  
Secretory Pathway ◽  
Nuclear Translocation ◽  
Inflammatory Responses ◽  
Mitogen Activated Protein Kinase ◽  
Mrna Levels ◽  
Phagocytic Cells ◽  
Mitogen Activated Protein ◽  
And Function

AbstractSoluble NSF attachment receptor (SNARE) proteins regulate the vesicle transport machinery in phagocytic cells. Within the secretory pathway, Sec22b is an ER-Golgi intermediate compartment (ERGIC)-resident SNARE that controls phagosome maturation and function in macrophages and dendritic cells. The secretory pathway controls the release of cytokines and may also impact the secretion of nitric oxide (NO), which is synthesized by the Golgi-active inducible nitric oxide synthase (iNOS). Whether ERGIC SNARE Sec22b controls NO and cytokine secretion, is unknown. Using bone marrow-derived dendritic cells (BMDC), we demonstrated that iNOS colocalizes with ERGIC/Golgi markers, notably Sec22b and its partner syntaxin-5 (Stx5), in the cytoplasm and at the phagosome. Pharmacological blockade of the secretory pathway hindered NO and cytokine release, and inhibited NF-κB translocation to the nucleus. Importantly, RNAi-mediated silencing of Sec22b revealed that NO and cytokine production were abrogated at the protein and mRNA levels. This correlated with deregulated mitogen-activated protein kinase signalling and reduced nuclear translocation of NF-κB. We also found that Sec22b co-occurs with NF-κB in both the cytoplasm and nucleus, pointing to a role for this SNARE in the shuttling of NF-κB. Collectively, our data unveiled a novel function for the ER-Golgi, and its resident SNARE Sec22b, in the production and release of inflammatory mediators.

scholarly journals Identification and analysis of circulating long non-coding RNAs with high significance in diabetic cardiomyopathy

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Tarun Pant ◽  
Anuradha Dhanasekaran ◽  
Ming Zhao ◽  
Edward B. Thorp ◽  
Joseph M. Forbess ◽  
...  
Keyword(s):  
Cardiac Function ◽  
Diabetic Cardiomyopathy ◽  
Bioinformatic Analysis ◽  
Mitogen Activated Protein Kinase ◽  
Diagnostic Biomarker ◽  
Diagnostic Biomarkers ◽  
Mitogen Activated Protein ◽  
Non Coding Rnas ◽  
Α Chain ◽  
Factor Α

AbstractDiabetic cardiomyopathy (DCM) lacks diagnostic biomarkers. Circulating long non-coding RNAs (lncRNAs) can serve as valuable diagnostic biomarkers in cardiovascular disease. To seek potential lncRNAs as a diagnostic biomarker for DCM, we investigated the genome-wide expression profiling of circulating lncRNAs and mRNAs in type 2 diabetic db/db mice with and without DCM and performed bioinformatic analyses of the deregulated lncRNA-mRNA co-expression network. Db/db mice had obesity and hyperglycemia with normal cardiac function at 6 weeks of age (diabetes without DCM) but with an impaired cardiac function at 20 weeks of age (DCM) on an isolated Langendorff apparatus. Compared with the age-matched controls, 152 circulating lncRNAs, 127 mRNAs and 3355 lncRNAs, 2580 mRNAs were deregulated in db/db mice without and with DCM, respectively. The lncRNA-mRNA co-expression network analysis showed that five deregulated lncRNAs, XLOC015617, AK035192, Gm10435, TCR-α chain, and MouselincRNA0135, have the maximum connections with differentially expressed mRNAs. Bioinformatic analysis revealed that these five lncRNAs were highly associated with the development and motion of myofilaments, regulation of inflammatory and immune responses, and apoptosis. This finding was validated by the ultrastructural examination of myocardial samples from the db/db mice with DCM using electron microscopy and changes in the expression of myocardial tumor necrosis factor-α and phosphorylated p38 mitogen-activated protein kinase in db/db mice with DCM. These results indicate that XLOC015617, AK035192, Gm10435, TCR-α chain, and MouselincRNA0135 are crucial circulating lncRNAs in the pathogenesis of DCM. These five circulating lncRNAs may have high potential as a diagnostic biomarker for DCM.

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