scholarly journals Integrated Metabolomics and Network Pharmacology Study on Immunoregulation Mechanisms ofPanax ginsengthrough Macrophages

2019 ◽  
Vol 2019 ◽  
pp. 1-14 ◽  
Author(s):  
Junjie Hao ◽  
Huangwanyin Hu ◽  
Jing Liu ◽  
Xuan Wang ◽  
Xiaoyi Liu ◽  
...  
Keyword(s):  
Network Pharmacology ◽  
Glutathione Metabolism ◽  
Macrophage Phenotype ◽  
Ginsenoside Re ◽  
E Coli ◽  
Choline Metabolism ◽  
Macrophage Phagocytosis ◽  
M2 Phenotype ◽  
Potential Biomarkers ◽  
Integrated Metabolomics

Panax ginseng(PG) is a widely used functional food and herbal with immunoregulation activity. Currently, immunoregulation studies of PG mainly focused on the specific actions of individual constituents. However, the integral immunoregulation mechanisms of PG need further research. In this study, an integrated metabolomics and network pharmacology approach were used to investigate it. High-content screening was used to evaluate macrophage phagocytosis activity of PG. Untargeted metabolomics profiling of murine macrophage cells with UHPLC-Q-TOF-MS and a multivariate data method were performed to discover the potential biomarkers and metabolic pathways. Then, a macrophage phenotype related “ingredients-targets-metabolites” network of PG was constructed using network pharmacology for further research. As a result, PG can significantly enhance macrophage phagocytosis of GFP-E. coli. A total of twenty potential biomarkers and ten main pathways for which levels changed markedly upon treatment were identified, including glycerophospholipid metabolism, glutathione metabolism, choline metabolism, and taurine metabolism. Twenty compounds of PG associated with metabolomic changes were selected by the network pharmacology analysis, including ginsenoside Re, ginsenoside Rg1, frutinone A, and kaempferol. The network pharmacology results also showed that PG can polarize macrophages to both M1 and M2 phenotype but may be prone to M2 phenotype. In conclusion, our results indicated that PG may be prone to polarize macrophages to M2 phenotype by mainly regulating the glutathione and choline metabolism, which was related to twenty compounds of PG.

scholarly journals Intestinal Metabolites Influence Macrophage Phagocytosis and Clearance of Bacterial Infection

2021 ◽  
Vol 11 ◽  
Author(s):  
Amy A. O’Callaghan ◽  
Elaine Dempsey ◽  
Namrata Iyer ◽  
Sarah Stiegeler ◽  
Kevin Mercurio ◽  
...  
Keyword(s):  
Bacterial Infection ◽  
Metabolic Flux ◽  
Marker Gene ◽  
Intestinal Lumen ◽  
Microbial Fermentation ◽  
Macrophage Phenotype ◽  
E Coli ◽  
Macrophage Phagocytosis ◽  
Infection Treatment ◽  
By Products

The metabolite-rich environment that is the intestinal lumen contains metabolic by-products deriving from microbial fermentation and host cell metabolism, with resident macrophages being constantly exposed to this metabolic flux. Succinate, lactate and itaconate are three metabolites secreted by primed macrophages due to a fragmented tri-carboxylic acid (TCA) cycle. Additionally, succinate and lactate are known by-products of microbial fermentation. How these metabolites impact biological functioning of resident macrophages particularly in response to bacterial infection remains poorly understood. We have investigated the potential influence of these metabolites on macrophage phagocytosis and clearance of Escherichia coli (E. coli) infection. Treatment of murine bone-marrow-derived macrophages (BMDMs) with succinate reduced numbers of intracellular E. coli early during infection, while lactate-treated BMDMs displayed no difference throughout the course of infection. Treatment of BMDMs with itaconate lead to higher levels of intracellular E. coli early in the infection with bacterial burden subsequently reduced at later time-points compared to untreated macrophages, indicative of enhanced engulfment and killing capabilities of macrophages in response to itaconate. Expression of engulfment mediators MARCKS, RhoB, and CDC42 were reduced or unchanged following succinate or lactate treatment and increased in itaconate-treated macrophages following E. coli infection. Nitric oxide (NO) levels varied while pro- and anti-inflammatory cytokines differed in secretory levels in all metabolite-treated macrophages post-infection with E. coli or in response to lipopolysaccharide (LPS) stimulation. Finally, the basal phenotypic profile of metabolite-treated macrophages was altered according to marker gene expression, describing how fluid macrophage phenotype can be in response to the microenvironment. Collectively, our data suggests that microbe- and host-derived metabolites can drive distinct macrophage functional phenotypes in response to infection, whereby succinate and itaconate regulate phagocytosis and bactericidal mechanisms, limiting the intracellular bacterial niche and impeding the pathogenesis of infection.

Abstract 1727: Apolipoprotein E (ApoE) Induces an Anti-inflammatory Phenotype in Macrophages

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Daniel Baitsch ◽  
Ralph Telgmann ◽  
Georg Varga ◽  
Carsten Muller-Tidow ◽  
Martine Bot ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Apolipoprotein E ◽  
Kinase Inhibitor ◽  
Plasma Cholesterol ◽  
Macrophage Phenotype ◽  
Anti Inflammatory ◽  
M2 Phenotype ◽  
Functional Phenotype ◽  
Expression And Activity ◽  
Phenotype Expression

Apolipoprotein E (apoE) exerts anti-atherogenic effects by promoting cholesterol efflux and hepatic lipoprotein clearance. However, apoE retains protective effects even under experimental settings, in which its influence on plasma cholesterol is negligible suggesting that this lipoprotein inhibits atherosclerosis independently from cholesterol transport. To gain further insight into mechanisms underlying apoE-mediated atheroprotection, we investigated its effect on the functional phenotype of RAW 264.7 macrophages overexpressing either of two apoE receptors: ApoER2/LRP8 or VLDL-R. Incubation of ApoER2/LRP8- or VLDL-R-expressing macrophages with apoE downregulated markers of pro-inflammatory M1 functional phenotype (expression and activity of iNOS, production of IL-12), whereas markers of anti-inflammatory M2 phenotype (expression and activity of arginase-I, production of IL-1RA) were upregulated. In addition, macrophage responses typical for M1 phenotype (migration, generation of reactive oxygen species, antibody-dependent cell cytotoxicity) were suppressed in ApoER2/LRP8- or VLDL-R-expressing cells in the presence of apoE. Finally, apoE prevented LPS- and IFN-γ-induced activation of ApoER2/LRP8- or VLDL-R-expressing macrophages as documented by reduced production of IL-12, TNF-α and MCP-1, reduced expression and activity of iNOS and COX2, and reduced activation and/or phosphorylation of NF-κB, IκB and STAT1. The modulatory effects of apoE on macrophage phenotype were inhibited by SB220025, a p38MAP kinase inhibitor, and PP1A, a tyrosine kinase inhibitor. Accordingly, apoE induced tyrosine kinase-dependent activation of p38MAP kinase in ApoER2/LRP8- or VLDL-R-expressing macrophages. Under in vivo conditions, apoE −/− mice transplanted with apoE-producing wild-type bone marrow presented with increased plasma IL-1RA levels. In addition, peritoneal macrophages from transplanted animals demonstrated enhanced M2 phenotype (increased IL-1RA production and CD206 expression). We conclude that apoE signalling over ApoER2/LRP8 or VLDL-R promotes macrophage conversion from pro-inflammatory M1 to anti-inflammatory M2 phenotype. This effect may represent a novel anti-atherogenic activity of apoE.

Abstract 11059: Role of Sirtuin 6 in Macrophage Polarization and Cardiac Repair in Diabetes

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Rajarajan A Thandavarayan ◽  
Darukeshwara Joladarashi ◽  
Sahana S Babu ◽  
Garikipati V Srikanth ◽  
Alexander R Mackie ◽  
...  
Keyword(s):  
Macrophage Polarization ◽  
Experimental Studies ◽  
Peritoneal Macrophages ◽  
Left Ventricular ◽  
Cardiac Repair ◽  
Raw 264.7 Cells ◽  
Mouse Bone Marrow ◽  
Macrophage Phenotype ◽  
Intramyocardial Injection ◽  
M2 Phenotype

Clinical and experimental studies provide evidence that metabolic and inflammatory pathways are functionally interconnected to cardiovascular diseases. Dynamic changes in macrophage activation [classical M1 activation (promote inflammation) or alternative M2 activation (promote wound healing)], in response to various stress signals, modulate cardiac physiopathology in diabetes. Sirtuin 6 (SIRT6), a NAD-dependent nuclear deacetylase plays an important role in genomic stability, cellular metabolism, stress response and aging. However, the mechanism by which SIRT6 activity affects macrophage phenotype and cardiac function in diabetes is still unexplored. Mouse bone marrow-derived macrophages (BMM) exposed to high glucose (HG, 25mM D-glucose) showed reduced expression of SIRT6 as compared to low glucose (LG, 5mM D-glucose)- and osmotic control (OC, 5mM D-glucose+20mM D-mannitol)-treated cells, associated with increased expression of proinflammatory cytokine and transcription factors (NFkb, c-JUN, FOXO, SP1 and STAT1). In addition, SIRT6 level was reduced in peritoneal macrophages of both diabetic models (streptozotocin-induced and db/db mice) as compared to non-diabetic mice. SIRT6 knockdown in RAW 264.7 cells exaggerated inflammatory response when exposed to HG. In contrast, IL-4-induced increase in mRNA expression of macrophage M2 phenotype markers like Arg1, Chi4l4, Retnla and IRS-2, but not IRS-1 expression was repressed suggesting that alternative macrophage (M2) phenotype was defective in SIRT6 deficient BM-macrophages under HG condition. SIRT6 protein expression was low in myocardial infarction-induced (MI) and diabetes-affected hearts. Interestingly, mice receiving intramyocardial injection of SIRT6-deficient macrophages showed further deterioration in left ventricular function, post-MI. Taken together, these data highlight a role for SIRT6 in regulating the balance of M1/M2 polarization, therefore, modulate macrophage mediated cardiac repair and regeneration in numerous inflammatory disease states including diabetes

scholarly journals Molecular Characterization of Advanced Colorectal Cancer Using Serum Proteomics and Metabolomics

2021 ◽  
Author(s):  
Jun Rao ◽  
Xianghui Wan ◽  
Fangfang Tou ◽  
Qinsi He ◽  
Aihua Xiong ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Molecular Characterization ◽  
Arachidonic Acid Metabolism ◽  
Health Concern ◽  
Glutathione Metabolism ◽  
Serum Samples ◽  
Serum Proteomics ◽  
Potential Biomarkers ◽  
Tof Ms

Abstract Introduction Colorectal cancer (CRC) is a growing public health concern with high mortality rate. However, there are no valid diagnostic biomarkers and few therapeutic strategies available for CRC, especially advanced CRC, since the pathogenic mechanisms remain poorly understood. Objective To comprehensively reveal molecular characterization of advanced CRC, we applied integrated proteomic and metabolomic analyses on serum samples from 20 patients with CRC at stage III or IV. Methods In the present study, we took advantage of nanoscale liquid chromatography and quadrupole time-of-flight tandem mass spectrometry (nanoLC/Q-TOF-MS/MS) and ultraperformance LC/Q-TOF-MS/MS technologies. Results Overall, 551 proteins and 719 metabolites were identified in those serum samples, respectively. Hierarchical clustering analysis indicated much more remarkable diversity in proteomic profiles than metabolomic profiles. Further functional analysis suggested that ten key pathways associated with cancer cell metabolism were dissected including glycolysis/gluconeogenesis, biosynthesis of amino acids, glutathione metabolism, and arachidonic acid metabolism, based on which protein-protein interaction network analysis was thus constructed with 80 proteins and 21 metabolites. Moreover, the regulatory network in advanced CRC was established according to correlation analysis, indicating conserved roles of metabolome and lipids & lipid like molecules in human serum. Nevertheless, three metabolites and two proteins including hydroquinone, leucenol and sphingomyelin were supposed to be potential biomarkers, which were determined to be positively and significantly correlated with CEA and/or CA 19-9.Conclusions Altogether, our work not only extended our understanding on the physiopathology of advanced CRC, but provided potential biomarkers to improve the accuracy of the diagnosis and monitoring of the syndrome.

scholarly journals The antimicrobial peptide S100A8/A9 produced by airway epithelium functions as a potent and direct regulator of macrophage phenotype and function

2021 ◽  
pp. 2002732
Author(s):  
Wioletta Skronska-Wasek ◽  
Sibel Durlanik ◽  
Huy Quang Le ◽  
Victoria Schroeder ◽  
Kerstin Kitt ◽  
...  
Keyword(s):  
Epithelial Cell ◽  
Airway Epithelium ◽  
Airway Epithelial Cell ◽  
Macrophage Phenotype ◽  
Airway Epithelial ◽  
Phagocytic Capacity ◽  
Macrophage Phagocytosis ◽  
Depth Analysis ◽  
And Function

Elevated counts of alveolar macrophages and attenuated phagocytic capacity are associated with COPD. Factors governing macrophage phagocytosis are poorly understood. In this study we aimed to compare the influence of airway epithelial cell secretions from COPD and nonCOPD subjects on macrophage phagocytic activity, and the role of antimicrobial peptides (AMPs).Supernatants from nonCOPD and COPD small airway epithelial cell (SAEC) cultures exposed to Haemophilus influenzae (NTHi), were applied to human monocyte-derived macrophages (MDM) for assessment of their influence on phagocytosis. SAECs were analysed for changes in AMP expression by qRT-PCR and the influence of select AMPs on macrophage phenotype and function was assessed by flow cytometry and metabolic activity assay.Secretions from the apical and basolateral surface of NTHi-exposed SAECs from nonCOPD donors elicited superior phagocytic capacity of MDMs. Moreover, NTHi exposure led to a rapid increase in expression of a range of AMPs by nonCOPD SAECs, but this response was delayed in COPD SAECs. We demonstrate that treatment with AMPs β-defensin 2 and S100A8/A9 improved the phagocytic capacity of MDMs. In depth analysis of S100A8/A9 influence of MDMs revealed a role of this AMP in macrophage phenotype and function. Furthermore, we show that the expression of S100A8 and S100A9 is directly regulated by WNT/β-catenin signalling activity, a known deregulated pathway in COPD.In conclusion, for the first time, we demonstrate that airway epithelium from COPD subjects has a reduced capacity to support the phagocytic function of macrophages in response to acute NTHi exposure, and we identify the WNT/β-catenin signalling-modulated and epithelium-derived S100A8/A9 as a potent regulator of macrophage phenotype and function.

scholarly journals Mechanism of Paeoniflorin on ANIT-Induced Cholestatic Liver Injury Using Integrated Metabolomics and Network Pharmacology

2021 ◽  
Vol 12 ◽  
Author(s):  
Lisheng Chen ◽  
Xu Zhao ◽  
Shizhang Wei ◽  
Xiao Ma ◽  
Honghong Liu ◽  
...  
Keyword(s):  
Liver Injury ◽  
Western Blotting ◽  
Interaction Network ◽  
Network Pharmacology ◽  
Bile Acid Metabolism ◽  
Signal Pathways ◽  
Hepatic Diseases ◽  
Biochemical Indices ◽  
Cholestatic Liver Injury ◽  
Potential Biomarkers

Background: Paeoniflorin (PF), the major active compound isolated from the roots of Paeonia lactiflora Pall., has been used in the treatment of severe hepatic diseases for several decades and displays bright prospects in liver protective effect. However, its biological mechanism that regulates bile acid metabolism and cholestatic liver injury has not been fully elucidated. Our study aims to investigate the mechanism by which PF in the treatment of cholestatic liver injury using a comprehensive approach combining metabolomics and network pharmacological analysis.Methods: The hepatoprotective effect of PF against cholestasis liver injury, induced by α-naphthylisothiocyanate (ANIT), was evaluated in rats. The serum biochemical indices including ALT, AST, TBA, TBIL, ALP, ALB, and the pathological characteristics of the liver were analyzed. Moreover, UHPLC-Q-TOF was performed to explore the feces of rats with ANIT-induced cholestatic liver injury treated with PF and the potential biomarkers were screened by metabolomics. The targets for the regulation of potential biomarkers by PF were screened by network pharmacology, and then the relevant key targets were verified by immunohistochemical and western blotting methods.Results: PF significantly improved serum indexes and alleviated liver histological damage. Metabolomics analyses showed that the therapeutic effect of PF is mainly associated with the regulation of 13 metabolites involved in 16 metabolic pathways. The “PF-targets-metabolites” interaction network was constructed, and then five key targets including CDC25B, CYP2C9, MAOB, mTOR, and ABCB1 that regulated the potential biomarkers were obtained. The above five targets were further verified by immunohistochemistry and western blotting, and the results showed that PF significantly improved the expression of key proteins regulating these biomarkers.Conclusion: Our study provides direct evidence for the modulatory properties of PF treatment on ANIT-induced cholestatic liver injury using metabolomics and network pharmacology analyses. PF exhibits favorable pharmacological effect by regulating related signal pathways and key targets for biomarkers. Therefore, these findings may help better understand the complex mechanisms and provide a new and effective approach to the treatment of cholestatic liver injury.

Cellular and Humoral Systemic and Mucosal Immune Responses Stimulated by an Oral Polybacterial Immunomodulator in Patients with Chronic Urinary Tract Infections

2005 ◽  
Vol 18 (3) ◽  
pp. 457-473 ◽  
Author(s):  
S. Marinova ◽  
P. Nenkov ◽  
R. Markova ◽  
S. Nikolaeva ◽  
R. Kostadinova ◽  
...  
Keyword(s):  
Urinary Tract ◽  
Immune Responses ◽  
Urinary Tract Infections ◽  
Specific Antigen ◽  
Electron Microscopic ◽  
E Coli ◽  
Macrophage Phagocytosis ◽  
Mucosal Immune Responses ◽  
Pre Treatment ◽  
Tract Infections

An oral polybacterial immunomodulator Urostim (U), composed of killed cells and their lysates from E. coli expressing type 1 and P-pili, E. coli Re mutant, P. mirabilis, K. pneumoniae and E. faecalis was created for immunoprophylaxis and immunotherapy of urinary tract infections (UTIs). In experimental animal models, the stimulating effect of U on lymphocyte functional activity, macrophage phagocytosis and antibody producing cells, was established. In this study the immuno-modulating effects of U on the proliferating capacity and ultrastructural morphologic changes of lymphocytes, cytokine production and specific systemic humoral and mucosal immune responses in patients with UTIs have been evaluated. Patients enrolled in the study, received orally 50 mg U daily for a period of three months. On days 0,30 and 90 a quantitative analysis was performed on lymphoproliferative responses to polyclonal mitogens, IL-2 and the specific antigen U, the production of specific serum and saliva IgA, IgM and IgG antibodies to all components of U and the concentration of pro-inflammatory cytokines. There was significant improvement of non-specific and specific lymphoproliferative responses on days 30 and 90 after the onset of treatment with U, confirmed by electron-microscopic studies. The highest concentrations of serum proinflammatory cytokines TNF-α, IL-1β, and IL-6 were registered at baseline followed by a decrease until the end of the observation period. This finding correlates with the gradual decrease of immune activation as measured by the spontaneous lymphocyte proliferation. Data from the production of specific antibacterial antibodies in serum and saliva show two types of reactions. The first type was registered in patients with low pre-treatment levels in whom the concentration of specific antibodies increased on days 30 and 90. The second type of reaction was observed in patients with high pre-treatment levels, which dropped on day 30 and were usually followed by an increase at the end of the study. These results provide evidence for the immuno-modulating effect of U. Our data show that the oral administration of the polybacterial immunomodulator Urostim stimulates adequate cellular and humoral systemic and mucosal immune responses in patients with chronic UTIs.

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