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 Luteolin-3′-O-Phosphate Inhibits Lipopolysaccharide-Induced Inflammatory Responses by Regulating NF-κB/MAPK Cascade Signaling in RAW 264.7 Cells

Molecules ◽  
2021 ◽  
Vol 26 (23) ◽  
pp. 7393
Author(s):  
Jung-Hwan Kim ◽  
Tae-Jin Park ◽  
Jin-Soo Park ◽  
Min-Seon Kim ◽  
Won-Jae Chi ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Inflammatory Responses ◽  
Mitogen Activated Protein Kinase ◽  
Inflammatory Activity ◽  
Raw 264.7 Cells ◽  
Raw 264.7 ◽  
Mitogen Activated Protein ◽  
Anti Inflammatory

Luteolin (LT), present in most plants, has potent anti-inflammatory properties both in vitro and in vivo. Furthermore, some of its derivatives, such as luteolin-7-O-glucoside, also exhibit anti-inflammatory activity. However, the molecular mechanisms underlying luteolin-3′-O-phosphate (LTP)-mediated immune regulation are not fully understood. In this paper, we compared the anti-inflammatory properties of LT and LTP and analyzed their molecular mechanisms of action; we obtained LTP via the biorenovation of LT. We investigated the anti-inflammatory activities of LT and LTP in macrophage RAW 264.7 cells. We confirmed from previously reported literature that LT inhibits the production of nitric oxide and prostaglandin E2, as well as the expression of inducible NO synthetase and cyclooxygenase-2. In addition, expressions of inflammatory genes and mediators, such as tumor necrosis factor-α, interleukin-6, and interleukin-1β, were suppressed. LTP showed anti-inflammatory activity similar to LT, but better anti-inflammatory activity in all the experiments, while also inhibiting mitogen-activated protein kinase and nuclear factor-kappa B more effectively than LT. At a concentration of 10 μM, LTP showed differences of 2.1 to 44.5% in the activity compared to LT; it also showed higher anti-inflammatory activity. Our findings suggest that LTP has stronger anti-inflammatory activity than LT.

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.

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.

P0358HYDROXYCHLOROQUINE PREVENTS ANTI-GBM GLOMERULONEPHRITIS IN RATS

2020 ◽  
Vol 35 (Supplement_3) ◽  
Author(s):  
Miki Torigoe ◽  
Yoko Obata ◽  
Hiro Inoue ◽  
Kenta Torigoe ◽  
Akira Kinoshita ◽  
...  
Keyword(s):  
Renal Function ◽  
P38 Mapk ◽  
Therapeutic Potential ◽  
Mitogen Activated Protein Kinase ◽  
Interferon Α ◽  
Crescent Formation ◽  
Chemotactic Protein ◽  
Mitogen Activated Protein ◽  
Anti Inflammatory ◽  
Factor Α

Abstract Background and Aims Anti-glomerular basement membrane (GBM) glomerulonephritis (GN), characterized by glomerular crescent formation, requires early treatment because of poor prognosis. Hydroxychloroquine (HCQ) is a well-known antimalarial drug. In addition, it has immunomodulatory, anti-inflammatory, and autophagy inhibitory effects and its recognized in the treatment of autoimmune disease such as SLE. However, its effect for anti-GBM GN is unknown. In this study, we investigated the effect of HCQ against anti-GBM GN in rats. Method 7 week old male, WKY rats were induced by the administration of anti-GBM serum (50μg/rat). We administered either HCQ (50mg/kg) or vehicle (Phosphate-buffered saline) from day 0 to day 7 after the induction of nephritis. Renal function was assessed by measuring serum creatinine, proteinuria, hematuria. Urine was collected for 24 hours on day 1, 3, 5, and 7. Rats were sacrificed on day 7 after induction of anti-GBM GN. Renal histological changes were assessed by PAS staining, and Masson trichrome stain, and macrophage was assessed by ED-1 stain. Mitogen-Activated Protein Kinase (MAPK) was evaluated by western blotting (WB) and inflammatory cytokines were evaluated by ELISA using urine. Results HCQ treatment suppressed renal function decline. Histologically, extracellular and intracellular cells were increased from day 1, fibrinoid necrosis and ED-1 positive cells were observed from day 3. Rats with anti-GBM GN had high levels of interferon-α, interleukin-6, monocyte chemotactic protein-1, and tumor necrosis factor-α. These changes were significantly suppressed by HCQ. In addition, HCQ suppressed phosphorylation of JNK/p38 MAPK. Conclusion Our study showed that HCQ could attenuate anti-GBM GN and have an anti-inflammatory effect by inhibiting JNK/p38 MAPK activation. HCQ may have therapeutic potential in anti-GBM GN.

scholarly journals Roles of peroxiredoxin II in the regulation of proinflammatory responses to LPS and protection against endotoxin-induced lethal shock

2007 ◽  
Vol 204 (3) ◽  
pp. 583-594 ◽  
Author(s):  
Chul-Su Yang ◽  
Dong-Seok Lee ◽  
Chang-Hwa Song ◽  
Se-Jin An ◽  
Shengjin Li ◽  
...  
Keyword(s):  
Inflammatory Responses ◽  
Nicotinamide Adenine Dinucleotide Phosphate ◽  
Nuclear Factor Κb ◽  
Negative Regulator ◽  
Mitogen Activated Protein Kinase ◽  
Host Responses ◽  
Enhanced Sensitivity ◽  
Mitogen Activated Protein ◽  
Lethal Shock ◽  
Deficient Mice

Mammalian 2-Cys peroxiredoxin II (Prx II) is a cellular peroxidase that eliminates endogenous H2O2. The involvement of Prx II in the regulation of lipopolysaccharide (LPS) signaling is poorly understood. In this report, we show that LPS induces substantially enhanced inflammatory events, which include the signaling molecules nuclear factor κB and mitogen-activated protein kinase (MAPK), in Prx II–deficient macrophages. This effect of LPS was mediated by the robust up-regulation of the reactive oxygen species (ROS)–generating nicotinamide adenine dinucleotide phosphate (NADPH) oxidases and the phosphorylation of p47phox. Furthermore, challenge with LPS induced greater sensitivity to LPS-induced lethal shock in Prx II–deficient mice than in wild-type mice. Intravenous injection of Prx II–deficient mice with the adenovirus-encoding Prx II gene significantly rescued mice from LPS-induced lethal shock as compared with the injection of a control virus. The administration of catalase mimicked the reversal effects of Prx II on LPS-induced inflammatory responses in Prx II–deficient cells, which suggests that intracellular H2O2 is attributable, at least in part, to the enhanced sensitivity to LPS. These results indicate that Prx II is an essential negative regulator of LPS-induced inflammatory signaling through modulation of ROS synthesis via NADPH oxidase activities and, therefore, is crucial for the prevention of excessive host responses to microbial products.

scholarly journals Discovery of Novel Pterostilbene Derivatives That Might Treat Sepsis by Attenuating Oxidative Stress and Inflammation through Modulation of MAPKs/NF-κB Signaling Pathways

Antioxidants ◽  
2021 ◽  
Vol 10 (9) ◽  
pp. 1333
Author(s):  
Mengyuan Fang ◽  
Tingfeng Zou ◽  
Xiaoxiao Yang ◽  
Zhen Zhang ◽  
Peichang Cao ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Inflammatory Responses ◽  
Nuclear Factor Κb ◽  
Severe Trauma ◽  
Mrna Levels ◽  
Raw264.7 Macrophages ◽  
Life Threatening ◽  
Anti Inflammatory ◽  
Factor Α ◽  
Oxide Synthase

Sepsis remains one of the most common life-threatening illnesses that is characterized by a systemic inflammatory response syndrome (SIRS) and usually arises following severe trauma and various septic infections. It is still in urgent need of new effective therapeutic agents, and chances are great that some candidates can be identified that can attenuate oxidative stress and inflammatory responses. Pterostilbene, which exerts attractive anti-oxidative and anti-inflammatory activities, is a homologue of natural polyphenolic derivative of resveratrol. Starting from it, we have made several rounds of rational optimizations. Firstly, based on the strategy of pharmacophore combination, indanone moiety was introduced onto the pterostilbene skeleton to generate a novel series of pterostilbene derivatives (PIF_1–PIF_16) which could possess both anti-oxidative and anti-inflammatory activities for sepsis treatment. Then, all target compounds were subjected to their structure–activity relationships (SAR) screening of anti-inflammatory activity in mouse mononuclear macrophage RAW264.7 cell line, and their cytotoxicities were determined after. Finally, an optimal compound, PIF_9, was identified. It decreased the mRNA levels of lipopolysaccharide (LPS)-induced interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), inducible nitric oxide synthase (iNOS), and cyclooxygenase 2 (COX2). We also found that the anti-inflammatory effects might be contributed by its suppression on the nuclear factor-κB (NF-κB) and MAPKs signaling pathway. Moreover, PIF_9 also demonstrated potent anti-oxidative activity in RAW264.7 macrophages and the sepsis mouse model. Not surprisingly, with the benefits mentioned above, it ameliorated LPS-induced sepsis in C57BL/6J mice and reduced multi-organ toxicity. Taken together, PIF_9 was identified as a potential sepsis solution, targeting inflammation and oxidative stress through modulating MAPKs/NF-κB.

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