scholarly journals Histatin-1 Attenuates LPS-Induced Inflammatory Signaling in RAW264.7 Macrophages

2021 ◽  
Vol 22 (15) ◽  
pp. 7856
Author(s):  
Sang Min Lee ◽  
Kyung-No Son ◽  
Dhara Shah ◽  
Marwan Ali ◽  
Arun Balasubramaniam ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Cytokine Production ◽  
Inflammatory Responses ◽  
Critical Role ◽  
Mapk Signaling ◽  
Response To Treatment ◽  
No Production ◽  
Inflammatory Signaling ◽  
Raw264.7 Macrophages ◽  
Inflammatory Mediator Production

Macrophages play a critical role in the inflammatory response to environmental triggers, such as lipopolysaccharide (LPS). Inflammatory signaling through macrophages and the innate immune system are increasingly recognized as important contributors to multiple acute and chronic disease processes. Nitric oxide (NO) is a free radical that plays an important role in immune and inflammatory responses as an important intercellular messenger. In addition, NO has an important role in inflammatory responses in mucosal environments such as the ocular surface. Histatin peptides are well-established antimicrobial and wound healing agents. These peptides are important in multiple biological systems, playing roles in responses to the environment and immunomodulation. Given the importance of macrophages in responses to environmental triggers and pathogens, we investigated the effect of histatin-1 (Hst1) on LPS-induced inflammatory responses and the underlying molecular mechanisms in RAW264.7 (RAW) macrophages. LPS-induced inflammatory signaling, NO production and cytokine production in macrophages were tested in response to treatment with Hst1. Hst1 application significantly reduced LPS-induced NO production, inflammatory cytokine production, and inflammatory signaling through the JNK and NF-kB pathways in RAW cells. These results demonstrate that Hst1 can inhibit LPS-induced inflammatory mediator production and MAPK signaling pathways in macrophages.

scholarly journals Reversal of the Inflammatory Responses in Fabry Patient iPSC-Derived Cardiovascular Endothelial Cells by CRISPR/Cas9-Corrected Mutation

2021 ◽  
Vol 22 (5) ◽  
pp. 2381
Author(s):  
Hui-Yung Song ◽  
Yi-Ping Yang ◽  
Yueh Chien ◽  
Wei-Yi Lai ◽  
Yi-Ying Lin ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Inflammatory Responses ◽  
Late Onset ◽  
Critical Role ◽  
Vascular Complications ◽  
Digital Pcr ◽  
Mapk Signaling ◽  
Autophagic Flux ◽  
Fabry Patient ◽  
Genomic Editing

The late-onset type of Fabry disease (FD) with GLA IVS4 + 919G > A mutation has been shown to lead to cardiovascular dysfunctions. In order to eliminate variations in other aspects of the genetic background, we established the isogenic control of induced pluripotent stem cells (iPSCs) for the identification of the pathogenetic factors for FD phenotypes through CRISPR/Cas9 genomic editing. We adopted droplet digital PCR (ddPCR) to efficiently capture mutational events, thus enabling isolation of the corrected FD from FD-iPSCs. Both of these exhibited the characteristics of pluripotency and phenotypic plasticity, and they can be differentiated into endothelial cells (ECs). We demonstrated the phenotypic abnormalities in FD iPSC-derived ECs (FD-ECs), including intracellular Gb3 accumulation, autophagic flux impairment, and reactive oxygen species (ROS) production, and these abnormalities were rescued in isogenic control iPSC-derived ECs (corrected FD-ECs). Microarray profiling revealed that corrected FD-derived endothelial cells reversed the enrichment of genes in the pro-inflammatory pathway and validated the downregulation of NF-κB and the MAPK signaling pathway. Our findings highlighted the critical role of ECs in FD-associated vascular dysfunctions by establishing a reliable isogenic control and providing information on potential cellular targets to reduce the morbidity and mortality of FD patients with vascular complications.

scholarly journals 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 ◽  
2019 ◽  
Vol 8 (11) ◽  
pp. 582 ◽  
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.

scholarly journals Pulmonary Hypertension Associated With Scleroderma and Connective Tissue Disease: Potential Molecular and Cellular Targets

2017 ◽  
Vol 16 (2) ◽  
pp. 61-67
Author(s):  
Maria Trojanowska
Keyword(s):  
Pulmonary Hypertension ◽  
Connective Tissue ◽  
Connective Tissue Disease ◽  
Lupus Erythematosus ◽  
Molecular Mechanisms ◽  
Critical Role ◽  
Connective Tissue Diseases ◽  
Clinical Manifestations ◽  
Response To Treatment ◽  
Organ Systems

Systemic sclerosis (SSc) is characterized by autoimmunity, small-vessel vasculopathy, and fibrosis causing damage in multiple organ systems. Pulmonary arterial hypertension (PAH) is a serious and often fatal complication of SSc, occurring in patients with the limited (lcSSc) and diffuse (dcSSc) forms of the disease and affecting 8% to 15% of patients.12 While pulmonary hypertension associated with connective tissue disease (CTD-PAH) has similar clinical features as idiopathic PAH, 1-year survival and freedom from hospitalization are lower in CTD-PAH.3 SSc-PAH has the worst 1-year survival rate at 82% compared with other connective tissue diseases, including systemic lupus erythematosus, mixed connective tissue disease, and rheumatoid arthritis.34 Despite the recent progress in the development of disease-targeted therapies, patients with SSc-PAH have a poorer response to treatment and a worse prognosis than other subgroups of PAH.1 Autoimmunity and prolonged vasculopathy preceding the development of clinical manifestations of SSc-PAH may play a critical role in the poorer outcome of SSc-PAH patients.1 This article will provide an overview of the recent findings related to cellular and molecular mechanisms associated with the development of PAH, with an emphasis on SSc-PAH.

scholarly journals Modeling Inflammation in Zebrafish for the Development of Anti-inflammatory Drugs

2021 ◽  
Vol 8 ◽  
Author(s):  
Yufei Xie ◽  
Annemarie H. Meijer ◽  
Marcel J. M. Schaaf
Keyword(s):  
Immune System ◽  
Inflammatory Response ◽  
Molecular Mechanisms ◽  
Inflammatory Responses ◽  
Inflammatory Diseases ◽  
Critical Role ◽  
Model Systems ◽  
Trinitrobenzene Sulfonic Acid ◽  
Inflammatory Drugs ◽  
Anti Inflammatory

Dysregulation of the inflammatory response in humans can lead to various inflammatory diseases, like asthma and rheumatoid arthritis. The innate branch of the immune system, including macrophage and neutrophil functions, plays a critical role in all inflammatory diseases. This part of the immune system is well-conserved between humans and the zebrafish, which has emerged as a powerful animal model for inflammation, because it offers the possibility to image and study inflammatory responses in vivo at the early life stages. This review focuses on different inflammation models established in zebrafish, and how they are being used for the development of novel anti-inflammatory drugs. The most commonly used model is the tail fin amputation model, in which part of the tail fin of a zebrafish larva is clipped. This model has been used to study fundamental aspects of the inflammatory response, like the role of specific signaling pathways, the migration of leukocytes, and the interaction between different immune cells, and has also been used to screen libraries of natural compounds, approved drugs, and well-characterized pathway inhibitors. In other models the inflammation is induced by chemical treatment, such as lipopolysaccharide (LPS), leukotriene B4 (LTB4), and copper, and some chemical-induced models, such as treatment with trinitrobenzene sulfonic acid (TNBS), specifically model inflammation in the gastro-intestinal tract. Two mutant zebrafish lines, carrying a mutation in the hepatocyte growth factor activator inhibitor 1a gene (hai1a) and the cdp-diacylglycerolinositol 3-phosphatidyltransferase (cdipt) gene, show an inflammatory phenotype, and they provide interesting model systems for studying inflammation. These zebrafish inflammation models are often used to study the anti-inflammatory effects of glucocorticoids, to increase our understanding of the mechanism of action of this class of drugs and to develop novel glucocorticoid drugs. In this review, an overview is provided of the available inflammation models in zebrafish, and how they are used to unravel molecular mechanisms underlying the inflammatory response and to screen for novel anti-inflammatory drugs.

scholarly journals IFN-mediated negative feedback supports bacteria class-specific macrophage inflammatory responses

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Rachel A Gottschalk ◽  
Michael G Dorrington ◽  
Bhaskar Dutta ◽  
Kathleen S Krauss ◽  
Andrew J Martins ◽  
...  
Keyword(s):  
Negative Feedback ◽  
Molecular Mechanisms ◽  
Cytokine Production ◽  
Inflammatory Responses ◽  
Type I ◽  
Gram Negative Bacteria ◽  
Gram Positive ◽  
Gram Negative

Despite existing evidence for tuning of innate immunity to different classes of bacteria, the molecular mechanisms used by macrophages to tailor inflammatory responses to specific pathogens remain incompletely defined. By stimulating mouse macrophages with a titration matrix of TLR ligand pairs, we identified distinct stimulus requirements for activating and inhibitory events that evoked diverse cytokine production dynamics. These regulatory events were linked to patterns of inflammatory responses that distinguished between Gram-positive and Gram-negative bacteria, both in vitro and after in vivo lung infection. Stimulation beyond a TLR4 threshold and Gram-negative bacteria-induced responses were characterized by a rapid type I IFN-dependent decline in inflammatory cytokine production, independent of IL-10, whereas inflammatory responses to Gram-positive species were more sustained due to the absence of this IFN-dependent regulation. Thus, disparate triggering of a cytokine negative feedback loop promotes tuning of macrophage responses in a bacteria class-specific manner and provides context-dependent regulation of inflammation dynamics.

Abstract 14810: Sam68 Promotes Nf-kb Signaling and Inflammation and Impedes the Recovery of Arterial Injury

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Shuling Han ◽  
Junlan Zhou ◽  
Gangjian Qin
Keyword(s):  
Inflammatory Cytokines ◽  
Molecular Mechanisms ◽  
Mononuclear Cells ◽  
Vascular Inflammation ◽  
Critical Role ◽  
Inflammatory Cells ◽  
Peritoneal Macrophages ◽  
Post Injury ◽  
Raw264.7 Macrophages ◽  
Tnf Α

Background: The role of Src-associated in mitosis 68 kDa (Sam68) protein in cardiovascular biology has not been studied. A recent report suggests that Sam68 suppresses TNF-α-mediated NF-kB activation. Since NF-kB plays a critical role in vascular inflammation and injury via generation of inflammatory cytokines and recruitment of inflammatory cells, we sought to dissect the molecular mechanism by which Sam68 regulates NF-kB signaling and its functional significance during vascular injury. Methods & Results: The endothelial denudation injury was induced in the carotid arteries of Sam68-null (Sam68 -/- ) and WT mice. Sam68 -/- mice displayed an accelerated re-endothelialization ( P <0.05 at day 5 post-injury) and attenuated neointima formation (by 2.2 folds, P <0.05, at day 14), which was associated with a reduced number of macrophages and lowered expression of pro-inflammatory cytokines (i.e., TNF-alpha, MCP-1 and IL-6) in the injured vessels. In cultured Raw264.7 macrophages, knockdown of Sam68 resulted in a significant reduction in the TNF-α-induced expression of TNF-α, MCP-1, and IL-6 and in the level of nuclear phospho-p65, which indicates attenuated NF-kB activation. These results were confirmed in peritoneal macrophages and macrophages differentiated from bone-marrow mononuclear cells of Sam68 -/- and WT mice. To identify molecular mechanisms, Raw264.7 cells were treated with TNF-α and Vehicle, followed by Sam68 co-immunoprecipitation and mass-spectrometric identification of the Sam68-interacting proteins. We found that TNF-α treatment results in altered interactions of Sam68 with 22 cytosolic, cytoskeletal, and nuclear proteins. Further experiments are under way to validate their involvement in the NF-kB signaling. Conclusions: Our results for the first time suggest that Sam68 promotes pro-inflammatory response in injured arteries and impedes recovery, and this effect may be partially attributable to the exaggerated NF-kB activity.

Abstract 124: Sam68 Impedes the Recovery of Arterial Injury by Augmenting Inflammatory Response

2015 ◽  
Vol 117 (suppl_1) ◽  
Author(s):  
Shuling Han ◽  
Junlan Zhou ◽  
Baron T Arnone ◽  
Dauren Biyashev ◽  
Chan Boriboun ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Inflammatory Cytokines ◽  
Molecular Mechanisms ◽  
Mononuclear Cells ◽  
Vascular Inflammation ◽  
Critical Role ◽  
Inflammatory Cells ◽  
Peritoneal Macrophages ◽  
Raw264.7 Macrophages ◽  
Tnf Α

Background: The role of Src-associated in mitosis 68 kDa (Sam68) in cardiovascular biology has not been studied. A recent report suggests that Sam68 suppresses TNF-α-induced NF-κB activation. Since NF-κB plays a critical role in vascular inflammation and injury via generation of inflammatory cytokines and recruitment of inflammatory cells, we sought to dissect the mechanism by which Sam68 regulates NF-κB signaling and its functional significance during vascular injury. Methods & Results: The endothelial denudation injury was induced in the carotid arteries of Sam68-/- and WT mice. Sam68-/- mice displayed an accelerated re-endothelialization and attenuated neointima hyperplasia, which was associated with a reduced number of macrophages and lowered expression of pro-inflammatory cytokines (i.e., TNF-α, IL-1β and IL-6) in the injured vessels. Importantly, the ameliorated vascular remodeling was recapitulated in WT mice after transplantation of bone marrow (BM) from Sam68-/- mice, suggesting beneficial role was attributed largely to BM-derived inflammatory cells. In cultured Raw264.7 macrophages, knockdown of Sam68 resulted in a significant reduction in the TNF-α-induced expression of TNF-α, IL-1β, and IL-6 and in the level of nuclear phospho-p65, indicating an attenuated NF-κB activation. These results were confirmed in peritoneal macrophages and macrophages differentiated from BM mononuclear cells of Sam68-/- and WT mice. To identify molecular mechanisms, Raw264.7 cells were treated with TNF-α and Vehicle, followed by Sam68 co-immunoprecipitation and mass-spec identification of Sam68-interacting proteins. Specifically, TNF-α treatment results in altered interactions of Sam68 with Filamin A (FLNA), a cytoskeleton protein known to be involved in NF-κB activation. Loss- and gain-of-function of Sam68 and FLNA suggest their mutual dependence in NF-κB activation and pro-inflammatory cytokine expression, and Sam68 is required for TRAF2-FLNA interaction. Conclusions: Our results for the first time suggest that Sam68 promotes pro-inflammatory response in injured arteries and impedes recovery, and this effect is attributed, in part, to the exaggerated NF-κB activity via Sam68-FLNA interaction and consequent TRAF2 stabilization.

Transforming growth factor-β-regulated expression of genes in macrophages implicated in the control of cholesterol homoeostasis

2006 ◽  
Vol 34 (6) ◽  
pp. 1141-1144 ◽  
Author(s):  
D.P. Ramji ◽  
N.N. Singh ◽  
P. Foka ◽  
S.A. Irvine ◽  
K. Arnaoutakis
Keyword(s):  
Growth Factor ◽  
Molecular Mechanisms ◽  
Transforming Growth Factor ◽  
Inflammatory Responses ◽  
Critical Role ◽  
Transforming Growth Factor Β ◽  
Crucial Importance ◽  
Expression Of Genes ◽  
Regulated Expression ◽  
Key Genes

The regulation of macrophage cholesterol homoeostasis is of crucial importance in the pathogenesis of atherosclerosis, an underlying cause of heart attack and stroke. Several recent studies have revealed a critical role for the cytokine TGF-β (transforming growth factor-β), a key regulator of the immune and inflammatory responses, in atherogenesis. We discuss here the TGF-β signalling pathway and its role in this disease along with the outcome of our recent studies on the action of the cytokine on the expression of key genes implicated in the uptake or efflux of cholesterol by macrophages and the molecular mechanisms underlying such regulation.

Effects of Shiranuhi flower extracts and fractions on lipopolysaccharide-induced inflammatory responses in murine RAW 264.7 cells

2018 ◽  
Vol 43 (4) ◽  
pp. 375-384 ◽  
Author(s):  
Chang-Gu Hyun ◽  
Min-Jin Kim ◽  
Sang Suk Kim ◽  
Ji Hye Ko ◽  
Young Il Moon ◽  
...  
Keyword(s):  
Cell Viability ◽  
Inflammatory Responses ◽  
Antioxidant Activities ◽  
Mapk Signaling ◽  
Raw 264.7 Cells ◽  
No Production ◽  
Raw 264.7 ◽  
Dependent Manner ◽  
Anti Inflammatory ◽  
Inflammatory Effect

Abstract Objective In this study, we evaluated the anti-inflammatory effect of Shiranuhi flower in RAW 264.7 cells. Methods The effects of the extracts and solvent fractions on cell viability and LPS-induced inflammatory responses were investigated in RAW 264.7 cells. Results The results showed that the ethyl acetate fraction (HEF) significantly decreased NO production in RAW 264.7 cells; however, cell viability was not affected. In addition, ELISA assay revealed that HEF significantly inhibited the productions of PGE2, TNF-α, and IL-6. As well, using Western blot analysis, it was observed that HEF significantly reduced the expression levels of iNOS and COX-2 in a dose dependent manner. Furthermore, we detected a reduced phosphorylation of mitogen-activated protein kinases such as p38, JNK, and ERK1/2. This indicates that HEF regulates LPS-induced inflammatory responses, at least in part, via suppressing the MAPK signaling pathway. Correlation analysis also showed that anti-inflammatory activities were highly correlated to antioxidant activities in this study. Characterization of the Shiranuhi flowers for flavonoid contents using HPLC showed varied quantity of narirutin and hesperidin. Conclusion Overall, the results demonstrate that HEF may be a potential anti-inflammatory agent. In addition, our findings contribute to understanding the molecular mechanism underlying the anti-inflammatory effect of Shiranuhi flower.

scholarly journals Neutrophil gelatinase-associated lipocalin as a potential therapeutic integrator of glycolipid metabolic and inflammatory signaling

2017 ◽  
Vol 4 (8) ◽  
pp. 2381 ◽  
Author(s):  
Junhua Gong ◽  
Rongtao Zhu ◽  
Jianping Gong ◽  
Kun He ◽  
Jiahai Chen
Keyword(s):  
Metabolic Syndrome ◽  
Therapeutic Target ◽  
Molecular Mechanisms ◽  
Inflammatory Responses ◽  
Subclinical Inflammation ◽  
Inflammatory Signaling ◽  
Potential Therapeutic Target ◽  
Alcoholic Fatty Liver ◽  
Neutrophil Gelatinase Associated Lipocalin ◽  
Neutrophil Gelatinase

Metabolic syndrome constitutes a group of metabolic conditions that increase the risk of developing diseases, including cardiovascular disease (CVD), non-alcoholic fatty liver disease (NAFLD), obesity and type 2 diabetes mellitus (T2DM) etc. Subclinical inflammation is a candidate etiological factor in the pathogenesis of metabolic syndrome and in the progression of related diseases. Although studies have revealed that subclinical inflammation was activated by intermediary products of basic metabolic processes, the cellular and molecular mechanisms in this association remain largely uncharacterized. Recently, increasing evidence suggests that neutrophil gelatinase-associated lipocalin (NGAL) not only plays a significant role in the glycolipid metabolism, but also modulates immune and inflammatory responses in macrophages. Taking together the ability of NGAL in metabolic and inflammatory signaling, these data suggest that NGAL may be a potential therapeutic target for metabolic and inflammatory signaling for intervention in human glycolipid metabolic disease. This review focuses on current knowledge of the integrators role of NGAL in both glucose and lipid metabolism and inflammatory signaling and discusses the potential therapeutic target in the treatment of glycolipid metabolic-related disease.

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