Chlojaponilactone B Attenuates Lipopolysaccharide-Induced Inflammatory Responses by Suppressing TLR4-Mediated ROS Generation and NF-κB Signaling Pathway

The lindenane-type sesquiterpenoid chlojaponilactone B (1), isolated from Chloranthus japonicus, has been reported to possess anti-inflammatory properties. The present study aimed to further explore the molecular mechanisms underlying the anti-inflammatory activity of 1. RNA-seq analyses revealed the significant changes in the expression levels of genes related to multiple inflammatory pathways upon treatment of lipopolysaccharide (LPS)-induced RAW 264.7 murine macrophages with 1. Real time PCR (RT-PCR) and Western blotting were used to confirm the modulations in the expression of essential molecules related to inflammatory responses. Compound 1 inhibited toll like receptor 4 (TLR4) and myeloid differentiation factor 88 (MyD88) activation upon LPS stimulation, influencing the expression of NF-κB and pro-inflammatory mediators. Molecular docking studies showed that 1 bound to TLR4 in a manner similar to that of TAK-242, a TLR4 inhibitor. Moreover, our results showed that 1 suppressed inflammatory responses by inhibiting TLR4 and subsequently decreasing reactive oxygen species (ROS) generation, downregulating the NF-κB, thus reducing the expression of the pro-inflammatory cytokines iNOS, NO, COX-2, IL-6 and TNF-α; these effects were similar to those of TAK-242. We proposed that 1 should be considered as a potential anti-inflammatory compound in future research.

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Impaired type I interferon activity and exacerbated inflammatory responses in severe Covid-19 patients

10.1101/2020.04.19.20068015 ◽

2020 ◽

Cited By ~ 70

Author(s):

Jérôme Hadjadj ◽

Nader Yatim ◽

Laura Barnabei ◽

Aurélien Corneau ◽

Jeremy Boussier ◽

...

Keyword(s):

Molecular Mechanisms ◽

Inflammatory Responses ◽

High Risk Population ◽

Type I ◽

Interferon Stimulated Genes ◽

Tnf Α ◽

Interferon Activity ◽

Anti Inflammatory ◽

Global Threat ◽

Necrosis Factor

AbstractBackgroundCoronavirus disease 2019 (Covid-19) is a major global threat that has already caused more than 100,000 deaths worldwide. It is characterized by distinct patterns of disease progression implying a diverse host immune response. However, the immunological features and molecular mechanisms involved in Covid-19 severity remain so far poorly known.MethodsWe performed an integrated immune analysis that included in-depth phenotypical profiling of immune cells, whole-blood transcriptomic and cytokine quantification on a cohort of fifty Covid19 patients with a spectrum of disease severity. All patient were tested 8 to 12 days following first symptoms and in absence of anti-inflammatory therapy.ResultsA unique phenotype in severe and critically ill patients was identified. It consists in a profoundly impaired interferon (IFN) type I response characterized by a low interferon production and activity, with consequent downregulation of interferon-stimulated genes. This was associated with a persistent blood virus load and an exacerbated inflammatory response that was partially driven by the transcriptional factor NFĸB. It was also characterized by increased tumor necrosis factor (TNF)-α and interleukin (IL)-6 production and signaling as well as increased innate immune chemokines.ConclusionWe propose that type-I IFN deficiency in the blood is a hallmark of severe Covid-19 and could identify and define a high-risk population. Our study provides a rationale for testing IFN administration combined with adapted anti-inflammatory therapy targeting IL-6 or TNF-α in most severe patients. These data also raise concern for utilization of drugs that interfere with the IFN pathway.

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Semisynthesis and Inhibitory Effects of Solidagenone Derivatives on TLR-Mediated Inflammatory Responses

Molecules ◽

10.3390/molecules23123197 ◽

2018 ◽

Vol 23 (12) ◽

pp. 3197 ◽

Cited By ~ 3

Author(s):

Irene Cuadrado ◽

Ángel Amesty ◽

Juan Cedrón ◽

Juan Oberti ◽

Ana Estévez-Braun ◽

...

Keyword(s):

Molecular Mechanisms ◽

Inflammatory Responses ◽

Spectroscopic Studies ◽

Peritoneal Macrophages ◽

Transcriptional Level ◽

Inhibitory Effects ◽

Structure Activity ◽

Tnf Α ◽

Anti Inflammatory ◽

Oxide Synthase

A series of nine derivatives (2–10) were prepared from the diterpene solidagenone (1) and their structures were elucidated by means of spectroscopic studies. Their ability to inhibit inflammatory responses elicited in peritoneal macrophages by TLR ligands was investigated. Compounds 5 and 6 showed significant anti-inflammatory effects, as they inhibited the protein expression of nitric oxide synthase (NOS-2), cyclooxygenase-2 (COX-2), and cytokine production (TNF-α, IL-6, and IL-12) induced by the ligand of TLR4, lipopolysaccharide (LPS), acting at the transcriptional level. Some structure–activity relationships were outlined. Compound 5 was selected as a representative compound and molecular mechanisms involved in its biological activity were investigated. Inhibition of NF-κB and p38 signaling seems to be involved in the mechanism of action of compound 5. In addition, this compound also inhibited inflammatory responses mediated by ligands of TLR2 and TLR3 receptors. To rationalize the obtained results, molecular docking and molecular dynamic studies were carried out on TLR4. All these data indicate that solidagenone derivative 5 might be used for the design of new anti-inflammatory agents.

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20-Hydroxy-3-Oxolupan-28-Oic Acid Attenuates Inflammatory Responses by Regulating PI3K–Akt and MAPKs Signaling Pathways in LPS-Stimulated RAW264.7 Macrophages

Molecules ◽

10.3390/molecules24030386 ◽

2019 ◽

Vol 24 (3) ◽

pp. 386 ◽

Cited By ~ 5

Author(s):

Yufeng Cao ◽

Fu Li ◽

Yanyan Luo ◽

Liang Zhang ◽

Shuya Lu ◽

...

Keyword(s):

Gene Expression ◽

Molecular Mechanisms ◽

Nuclear Translocation ◽

Inflammatory Responses ◽

Nuclear Factor Κb ◽

Activator Protein 1 ◽

Raw264.7 Macrophages ◽

Tnf Α ◽

Mitogen Activated Protein ◽

Anti Inflammatory

20-Hydroxy-3-oxolupan-28-oic acid (HOA), a lupane-type triterpene, was obtained from the leaves of Mahonia bealei, which is described in the Chinese Pharmacopeia as a remedy for inflammation and related diseases. The anti-inflammatory mechanisms of HOA, however, have not yet been fully elucidated. Therefore, the objective of this study was to characterize the molecular mechanisms of HOA in lipopolysaccharide (LPS)-stimulated RAW264.7 cells. HOA suppressed the release of nitric oxide (NO), pro-inflammatory cytokine tumor necrosis factor α (TNF-α), and interleukin 6 (IL-6) in LPS-stimulated RAW264.7 macrophages without affecting cell viability. Quantitative real-time reverse-transcription polymerase chain reaction (RT-qPCR) analysis indicated that HOA also suppressed the gene expression of inducible NO synthase (iNOS), TNF-α, and IL-6. Further analyses demonstrated that HOA inhibited the phosphorylation of upstream signaling molecules, including p85, PDK1, Akt, IκBα, ERK, and JNK, as well as the nuclear translocation of nuclear factor κB (NF-κB) p65. Interestingly, HOA had no effect on the LPS-induced nuclear translocation of activator protein 1 (AP-1). Taken together, these results suggest that HOA inhibits the production of cytokine by downregulating iNOS, TNF-α, and IL-6 gene expression via the downregulation of phosphatidylinositol 3-kinase (PI3K)/Akt and mitogen-activated protein kinases (MAPKs), and the inhibition of NF-κB activation. Our findings indicate that HOA could potentially be used as an anti-inflammatory agent for medical use.

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Ketamine’s effect on inflammation and kynurenine pathway in depression: A systematic review

Journal of Psychopharmacology ◽

10.1177/02698811211026426 ◽

2021 ◽

pp. 026988112110264

Author(s):

Emma Kopra ◽

Valeria Mondelli ◽

Carmine Pariante ◽

Naghmeh Nikkheslat

Keyword(s):

Systematic Review ◽

Animal Studies ◽

Bipolar Depression ◽

Strong Support ◽

Kynurenine Pathway ◽

Future Research ◽

Downstream Effects ◽

Tnf Α ◽

The Central Nervous System ◽

Anti Inflammatory

Background: Ketamine is a novel rapid-acting antidepressant with high efficacy in treatment-resistant patients. Its exact therapeutic mechanisms of action are unclear; however, in recent years its anti-inflammatory properties and subsequent downstream effects on tryptophan (TRP) metabolism have sparked research interest. Aim: This systematic review examined the effect of ketamine on inflammatory markers and TRP–kynurenine (KYN) pathway metabolites in patients with unipolar and bipolar depression and in animal models of depression. Methods: MEDLINE, Embase, and PsycINFO databases were searched on October 2020 (1806 to 2020). Results: Out of 807 initial results, nine human studies and 22 animal studies on rodents met the inclusion criteria. Rodent studies provided strong support for ketamine-induced decreases in pro-inflammatory cytokines, namely in interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α and indicated anti-inflammatory effects on TRP metabolism, including decreases in the enzyme indoleamine 2,3-dioxygenase (IDO). Clinical evidence was less robust with high heterogeneity between sample characteristics, but most experiments demonstrated decreases in peripheral inflammation including in IL-1β, IL-6, and TNF-α. Preliminary support was also found for reduced activation of the neurotoxic arm of the KYN pathway. Conclusion: Ketamine appears to induce anti-inflammatory effects in at least a proportion of depressed patients. Suggestions for future research include investigation of markers in the central nervous system and examination of clinical relevance of inflammatory changes.

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In Vitro Evaluation of the Anti-Inflammatory Effect of KMUP-1 and in Vivo Analysis of Its Therapeutic Potential in Osteoarthritis

Biomedicines ◽

10.3390/biomedicines9060615 ◽

2021 ◽

Vol 9 (6) ◽

pp. 615

Author(s):

Shang-En Huang ◽

Erna Sulistyowati ◽

Yu-Ying Chao ◽

Bin-Nan Wu ◽

Zen-Kong Dai ◽

...

Keyword(s):

Articular Cartilage ◽

Inflammatory Responses ◽

Therapeutic Potential ◽

Antioxidant Properties ◽

Serum Levels ◽

Gene Expressions ◽

Tnf Α ◽

Anti Inflammatory

Osteoarthritis is a degenerative arthropathy that is mainly characterized by dysregulation of inflammatory responses. KMUP-1, a derived chemical synthetic of xanthine, has been shown to have anti-inflammatory and antioxidant properties. Here, we aimed to investigate the in vitro anti-inflammatory and in vivo anti-osteoarthritis effects of KMUP-1. Protein and gene expressions of inflammation markers were determined by ELISA, Western blotting and microarray, respectively. RAW264.7 mouse macrophages were cultured and pretreated with KMUP-1 (1, 5, 10 μM). The productions of TNF-α, IL-6, MMP-2 and MMP- 9 were reduced by KMUP-1 pretreatment in LPS-induced inflammation of RAW264.7 cells. The expressions of iNOS, TNF-α, COX-2, MMP-2 and MMP-9 were also inhibited by KMUP-1 pretreatment. The gene expression levels of TNF and COX families were also downregulated. In addition, KMUP-1 suppressed the activations of ERK, JNK and p38 as well as phosphorylation of IκBα/NF-κB signaling pathways. Furthermore, SIRT1 inhibitor attenuated the inhibitory effect of KMUP-1 in LPS-induced NF-κB activation. In vivo study showed that KMUP-1 reduced mechanical hyperalgesia in monoiodoacetic acid (MIA)-induced rats OA. Additionally, KMUP-1 pretreatment reduced the serum levels of TNF-α and IL-6 in MIA-injected rats. Moreover, macroscopic and histological observation showed that KMUP-1 reduced articular cartilage erosion in rats. Our results demonstrated that KMUP-1 inhibited the inflammatory responses and restored SIRT1 in vitro, alleviated joint-related pain and cartilage destruction in vivo. Taken together, KMUP-1 has the potential to improve MIA-induced articular cartilage degradation by inhibiting the levels and expression of inflammatory mediators suggesting that KMUP-1 might be a potential therapeutic agent for OA.

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Oxymatrine inhibits lipopolysaccharide-induced inflammation by down-regulating Toll-like receptor 4/nuclear factor-kappa B in macrophages

Canadian Journal of Physiology and Pharmacology ◽

10.1139/cjpp-2014-0362 ◽

2015 ◽

Vol 93 (4) ◽

pp. 253-260 ◽

Cited By ~ 22

Author(s):

Yu Zhang ◽

Ruhong Yan ◽

Yae Hu

Keyword(s):

Nitric Oxide ◽

Interleukin 1 ◽

Chinese Herb ◽

Mrna Levels ◽

Nuclear Factor ◽

Toll Like Receptor ◽

Toll Like Receptor 4 ◽

Necrosis Factor Alpha ◽

Tnf Α ◽

Anti Inflammatory

Oxymatrine (OMT) is the quinolizidine alkaloid extracted from the Chinese herb Sophora flavescens Ait. that has many pharmacological effects and is used for the treatment of some inflammatory diseases. In this study, RAW264.7 cells and THP-1 differentiated macrophages were pretreated with various concentrations of OMT at 2 h prior to treatment with lipopolysaccharide (LPS) (1.0 μg/mL) for different durations. We detected the anti-inflammatory effect of OMT in LPS-stimulated macrophages and investigated the molecular mechanism. We showed that OMT pretreatment significantly inhibited the LPS-induced secretion of nitric oxide (NO), interleukin-1 beta (IL-1β), and tumor necrosis factor-alpha (TNF-α) in supernatant, attenuated the mRNA levels of inducible nitric oxide synthase (iNOS), IL-1β, TNF-α, and Toll-like receptor 4 (TLR4), increased TLR4 and phosphorylation of inhibitor of kappa B-alpha (p-IBα) in cytosol, and decreased the nuclear level of nuclear factor-κB (NF-κB) p65 in macrophages. In conclusion, OMT exerts anti-inflammatory properties in LPS-stimulated macrophages by down-regulating the TLR4/NF-κB pathway.

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Abstract 553: Siglec-1 (CD169) on Monocytes/Macrophages: A New Receptor For Extracellular Self-RNA in Triggering Inflammatory Responses via the Sheddase TACE/ADAM17

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvb.35.suppl_1.553 ◽

2015 ◽

Vol 35 (suppl_1) ◽

Author(s):

Hector A Cabrera-Fuentes ◽

Klaus T Preissner ◽

William A Boisvert

Keyword(s):

Inflammatory Cytokines ◽

Inflammatory Responses ◽

Transmembrane Protein ◽

Macrophage Polarization ◽

Extracellular Rna ◽

Tnf Α ◽

M1 Phenotype ◽

Phenotype Markers ◽

Anti Inflammatory

As an important component of atherosclerosis, monocytes/macrophages respond to external stimuli with rapid changes in their expression of many inflammation-related genes to undergo polarization towards the M1 (pro-inflammatory) or M2 (anti-inflammatory) phenotype. Although sialoadhesin (Sn), also known as SIGLEC-1 or CD169, is a transmembrane protein receptor expressed on monocytes and macrophages whether it has a role in macrophage polarization and ultimately, macrophage-driven atherogenesis, has not been investigated. We have previously shown that, independently of Toll-like receptor signaling, extracellular RNA (eRNA) could exert pro-thrombotic and pro-inflammatory properties in the cardiovascular system by inducing cytokine mobilization. In the current study, recombinant mouse macrophage CSF[[Unable to Display Character: –]]driven bone marrow-derived macrophage (BMDM) differentiation was found to be skewed towards the M1 phenotype by exposure of cells to eRNA. This resulted in up-regulation of inflammatory markers, whereas anti-inflammatory genes were significantly down-regulated by eRNA. Interestingly, eRNA was released from BMDM under hypoxia and induced TNF-α liberation by activating TNF-α converting enzyme (TACE) to provoke inflammation. Conversely, TNF-α promoted eRNA release, especially under hypoxia, feeding a vicious cycle of cell damage. Administration of RNase1 or TAPI (a TACE-inhibitor) prevented the production of inflammatory mediators. Murine BMDM isolated from mice deficient in sialoadhesin had the opposite reaction to eRNA treatment with a prominent down-regulation of pro-inflammatory cytokines/M1 phenotype markers, while anti-inflammatory cytokines/M2 phenotype markers were significantly raised. In keeping with the proposed role of eRNA as a pro-inflammatory “alarm signal”, these data further shed light on the role of eRNA in macrophage function in the context of chronic inflammatory diseases such as atherosclerosis. The identification of sialoadhesin as putative eRNA recognition site on macrophages may allow further investigation of the underlying mechanisms of eRNA-macrophage interaction and related signal transduction pathways. Siglec-1 thereby may provides a new target to treat eRNA-mediated vascular diseases.

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Protective Effects of Pelargonidin on Lipopolysaccharide-induced Hepatic Failure

Natural Product Communications ◽

10.1177/1934578x1801300114 ◽

2018 ◽

Vol 13 (1) ◽

pp. 1934578X1801300 ◽

Cited By ~ 1

Author(s):

Wonhwa Lee ◽

Yuri Lee ◽

Jaehong Kim ◽

Jong-Sup Bae

Keyword(s):

Liver Failure ◽

Molecular Mechanisms ◽

Biological Activities ◽

Serum Levels ◽

Primary Response ◽

Protective Effects ◽

Toll Like Receptor 4 ◽

Extracellular Signal ◽

Tnf Α ◽

Lps Treatment

Pelargonidin (PEL) is a well-known red pigment found in plants and has important biological activities that are potentially beneficial for human health. The aim of this study was to investigate the effect of PEL on lipopolysaccharide (LPS)-induced liver failure in mice, and to elucidate its underlying molecular mechanisms. Liver failure was induced by LPS (15 mg/kg, i.p) in mice, and 12 h later, they were treated intravenously with PEL. Administration of LPS significantly increased mortality, serum levels of alanine transaminase (ALT), aspartate transaminase (AST), and inflammatory cytokines, and expression of toll-like receptor 4 (TLR4) protein; PEL treatment effectively countered these effects of LPS. Further, LPS treatment markedly increased the expression of myeloid differentiation primary response gene 88 (MyD88), phosphorylation of p38, extracellular signal-regulated kinase (ERK), and c-Jun N-terminal kinase (JNK), and expressions of nuclear proteins, such as nuclear factor (NF)-κB and phosphorylated c-Jun. Additionally, LPS increased the serum levels of tumor necrosis factor (TNF)-α and interleukin (IL)-6. All these effects of LPS were attenuated by PEL. In addition, the LPS-mediated increase in the level of serum interferon (IFN)-β expression of the TLR-associated activator of IFN (TRIF) protein, and phosphorylation of IFN regulator factor 3 (IRF3) were reduced by PEL. Our results suggest that PEL attenuates LPS-induced liver damage by inhibition of the TLR-mediated inflammatory pathway and could be used to treat liver diseases.

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Pharmacological Inhibition of Caspase-8 Suppresses Inflammation-Induced Angiogenesis in the Cornea

Biomolecules ◽

10.3390/biom10020210 ◽

2020 ◽

Vol 10 (2) ◽

pp. 210

Author(s):

Yunzhe Tian ◽

He Li ◽

Xiuxing Liu ◽

Lihui Xie ◽

Zhaohao Huang ◽

...

Keyword(s):

Molecular Mechanisms ◽

Therapeutic Potential ◽

Corneal Neovascularization ◽

Caspase 8 ◽

Inhibitory Effects ◽

Toll Like Receptor 4 ◽

Pharmacological Inhibition ◽

Cytokines And Chemokines ◽

Tnf Α

Inflammation-induced angiogenesis is closely related to many diseases and has been regarded as a therapeutic target. Caspase-8 has attracted increasing attention for its immune properties and therapeutic potential in inflammatory disorders. The aim of our study is to investigate the clinical application of pharmacological inhibition of caspase-8 and the underlying molecular mechanisms in inflammation-induced angiogenesis in the cornea. A model of alkali burn (AB)-induced corneal neovascularization (CNV) in C57BL/6 wild-type (WT) mice and toll-like receptor 4 knockout (Tlr4-/-) mice was used. We found that AB increased caspase-8 activity and the pharmacological inhibition of caspase-8 exerted substantial inhibitory effects on CNV, with consistent decreases in caspase-8 activity, inflammatory cell infiltration, macrophage recruitment and activation, VEGF-A, TNF-α, IL-1β, MIP-1, and MCP-1 expression in the cornea. In vitro, caspase-8 mediated TLR4–dependent chemokines and VEGF-A production by macrophages. The TLR4 knockout significantly alleviated CNV, suppressed caspase-8 activity and downregulated expression of inflammatory cytokines and chemokines after AB. Taken together, these findings provide the first demonstration that the pharmacological inhibition of caspase-8 suppresses inflammation-induced angiogenesis and support the use of a pharmacological caspase-8 inhibitor as a novel clinical treatment for CNV and other angiogenic disorders.

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Phytosterols Suppress Phagocytosis and Inhibit Inflammatory Mediators via ERK Pathway on LPS-Triggered Inflammatory Responses in RAW264.7 Macrophages and the Correlation with Their Structure

Foods ◽

10.3390/foods8110582 ◽

2019 ◽

Vol 8 (11) ◽

pp. 582 ◽

Cited By ~ 5

Author(s):

Yuan ◽

Zhang ◽

Shen ◽

Jia ◽

Xie

Keyword(s):

Nitric Oxide ◽

Inflammatory Responses ◽

Ester Group ◽

No Production ◽

Raw264.7 Macrophages ◽

Extracellular Signal ◽

Tnf Α ◽

Anti Inflammatory ◽

Factor Α ◽

Oxide Synthase

Phytosterols, found in many commonly consumed foods, exhibit a broad range of physiological activities including anti-inflammatory effects. In this study, the anti-inflammatory effects of ergosterol, β-sitosterol, stigmasterol, campesterol, and ergosterol acetate were investigated in lipopolysaccharide (LPS)-induced RAW264.7 macrophages. Results showed that all phytosterol compounds alleviated the inflammatory reaction in LPS-induced macrophage models; cell phagocytosis, nitric oxide (NO) production, release of tumor necrosis factor-α (TNF-α), and expression and activity of pro-inflammatory mediator cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), and phosphorylated extracellular signal-regulated protein kinase (p-ERK) were all inhibited. The anti-inflammatory activity of β-sitosterol was higher than stigmasterol and campesterol, which suggests that phytosterols without a double bond on C-22 and with ethyl on C-24 were more effective. However, inconsistent results were observed upon comparison of ergosterol and ergosterol acetate (hydroxy or ester group on C-3), which suggest that additional research is still needed to ascertain the contribution of structure to their anti-inflammatory effects.

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