scholarly journals C-Reactive Protein and Cancer: Interpreting the Differential Bioactivities of Its Pentameric and Monomeric, Modified Isoforms

2021 ◽  
Vol 12 ◽  
Author(s):  
Lawrence A. Potempa ◽  
Ibraheem M. Rajab ◽  
Margaret E. Olson ◽  
Peter C. Hart
Keyword(s):  
Protein Structures ◽  
Biological Response ◽  
Biological Response Modifier ◽  
C Reactive Protein ◽  
Functional Activities ◽  
Reactive Protein ◽  
Anti Inflammatory ◽  
Cancer Agent

C-reactive protein (CRP) was first recognized in the 1940s as a protein that appeared in blood during acute episodes of infectious disease. Its presence and pharmacodynamics were found in essentially all diseases that involved tissue damage and inflammation. Identified as a major component of the innate, unlearned immunity, it became a useful diagnostic marker for the extent of inflammation during disease exacerbation or remission. Efforts to define its true biological role has eluded clear definition for over a half-century. Herein, a unifying concept is presented that explains both pro-inflammatory and anti-inflammatory activities of CRP. This concept involves the recognition and understanding that CRP can be induced to undergo a pronounced, non-proteolytic reorganization of its higher-level protein structures into conformationally distinct isomers with distinctive functional activities. This process occurs when the non-covalently associated globular subunits of the pentameric isoform (“pCRP”) are induced to dissociate into a monomeric isoform (“mCRP”). mCRP consistently and potently provides pro-inflammatory activation and amplification activities. pCRP provides weak anti-inflammatory activities consistent with low-level chronic inflammation. mCRP can spontaneously form in purified pCRP reagents in ways that are not immediately recognized during purification and certification analyses. By now understanding the factors that influence pCRP dissociate into mCRP, many published reports investigating CRP as a biological response modifier of host defense can be reevaluated to include a discussion of how each CRP isoform may have affected the generated results. Specific attention is given to in vitro and in vivo studies of CRP as an anti-cancer agent.

Discovery, in-vitro and in-vivo efficacy of an anti-inflammatory small molecule inhibitor of C-reactive protein

2021 ◽  
Author(s):  
Johannes Zeller ◽  
Karen Cheung Tung Shing ◽  
Tracy Nero ◽  
Guy Krippner ◽  
James McFadyen ◽  
...  
Keyword(s):  
Cell Activation ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Acute Ischemia ◽  
C Reactive Protein ◽  
Endothelial Cell Activation ◽  
Reactive Protein ◽  
Anti Inflammatory

Abstract C-reactive protein (CRP) is an acute phase protein. We recently identified a novel mechanism that leads to a conformational change from the native, pentameric structure (pCRP) to a pentameric intermediate (pCRP*) and ultimately to the monomeric form, mCRP, both being highly pro-inflammatory. This ‘CRP activation’ is mediated by binding of pCRP to activated/damaged cell membranes via exposed phosphocholine (PC) lipid head groups. We designed a low molecular weight pCRP – PC inhibitor, C10M. Binding assays and X-ray crystallography revealed direct, competitive binding of C10M to pCRP, blocking interaction with PC and thereby inhibiting formation of pCRP*/mCRP and their pro-inflammatory effects. The anti-inflammatory potential of C10M was confirmed in-vitro by various measures of leukocyte and endothelial cell activation and in-vivo in rat models of acute ischemia/reperfusion injury and hindlimb transplantation. In conclusion, inhibition of pCRP*/mCRP generation via the PC-mimicking compound C10M represents a promising, potentially broadly applicable anti-inflammatory therapy.

scholarly journals A review on the bio-functional roles of phospholipids from marine resources

Food Research ◽  
2021 ◽  
Vol 5 (5) ◽  
pp. 1-16
Author(s):  
M. Haq ◽  
S. Suraiya
Keyword(s):  
Synergistic Effects ◽  
Chemical Properties ◽  
Functional Roles ◽  
Functional Activities ◽  
Marine Phospholipids ◽  
Liver Functions ◽  
Anti Inflammatory ◽  
Unique Chemical

Marine phospholipids (PLs) rich in ω-3 polyunsaturated fatty acids (ω-3 PUFAs) have drawn keen interest recently among researchers and consumers and could be assumed as a “miracle drug”. Substantial amount of EPA and DHA, amazing and unique chemical properties and super bio-functional activities of marine PLs make it superior compared to terrestrial PLs, which lack long chain ω-3 PUFAs. Many comparative studies revealed that marine PLs showed higher health beneficial activities compared to PLs obtained from land sources. Marine PLs are not only beneficial in containing a high amount of ω-3 PUFAs but also in absorbing and assimilating ω-3 PUFAs in different tissues. Synergistic effects of PL compounds and ω-3 PUFAs in marine PLs showed super bio-functional performances like anti-atherosis and cardioprotective, anti-inflammatory, neuroprotective, immunological, and liver functions. A number of in vivo and in vitro studies on the administration of marine PLs extracted from fishes, mollusks, crustaceans, echinoderms reduced triacylglycerol (TAG) level and enhanced cardioprotective functions, demonstrated anti-inflammatory activity, reduced cell proliferation and tumor, increased cognitive functions and memory, and prevented hepatic damages. Therefore, this review paper provides detailed accounts on the present research status of critical biological and nutritional functions of marine ω-3 PUFAs rich phospholipids focusing on the origin, animal models, treatment, and roles.

scholarly journals Influence of apolipoprotein E genotype and dietary α-tocopherol on redox status and C-reactive protein levels in apolipoprotein E3 and E4 targeted replacement mice

2008 ◽  
Vol 100 (1) ◽  
pp. 44-53 ◽  
Author(s):  
Laia Jofre-Monseny ◽  
Patricia Huebbe ◽  
Inken Stange ◽  
Christine Boesch-Saadatmandi ◽  
Jan Frank ◽  
...  
Keyword(s):  
Apoe Genotype ◽  
Positive Association ◽  
Thiobarbituric Acid ◽  
Redox Status ◽  
C Reactive Protein ◽  
Cvd Risk ◽  
Reactive Protein ◽  
Antioxidant Defence System

The molecular basis of the positive association between apoE4 genotype and CVD remains unclear. There is direct in vitro evidence indicating that apoE4 is a poorer antioxidant relative to the apoE3 isoform, with some indirect in vivo evidence also available. Therefore it was hypothesised that apoE4 carriers may benefit from α-tocopherol (α-Toc) supplementation. Targeted replacement mice expressing the human apoE3 and apoE4 were fed with a diet poor (0 mg/kg diet) or rich (200 mg/kg diet) in α-Toc for 12 weeks. Neither apoE genotype nor dietary α-Toc exerted any effects on the antioxidant defence system, including glutathione, catalase, superoxide dismutase, glutathione peroxidase and glutathione reductase activities. In addition, no differences were observed in mitogen-induced lymphocyte proliferation. α-Toc concentrations were modestly higher in plasma and lower in tissues of apoE4 compared with apoE3 mice, with the greatest differences evident in the lung, suggesting that an apoE4 genotype may reduce α-Toc delivery to tissues. A tendency towards increased plasma F2-isoprostanes in apoE4 mice was observed, while liver thiobarbituric acid-reactive substances did not differ between apoE3 and apoE4 mice. In addition, C-reactive protein (CRP) concentrations were reduced in apoE4 mice indicating that this positive effect on CRP may in part negate the increased CVD risk associated with an apoE4 genotype.

scholarly journals C-Reactive Protein Adversely Alters the Protein–Protein Interaction of the Endothelial Isoform of Nitric Oxide Synthase

2010 ◽  
Vol 56 (8) ◽  
pp. 1345-1348 ◽  
Author(s):  
Simona Valleggi ◽  
Sridevi Devaraj ◽  
Mohan R Dasu ◽  
Ishwarlal Jialal
Keyword(s):  
Nitric Oxide ◽  
Nitric Oxide Synthase ◽  
Protein Interactions ◽  
Heat Shock Protein 90 ◽  
C Reactive Protein ◽  
Caveolin 1 ◽  
Reactive Protein ◽  
Oxide Synthase

BACKGROUND C-reactive protein (CRP) inhibits the activity of the endothelial isoform of nitric oxide synthase (eNOS) via uncoupling of the enzyme both in vitro and in vivo. eNOS activity appears to be related in part to its interaction with other cellular proteins, including heat shock protein 90 (Hsp90), caveolin-1, and porin. In this study, we examined the effect of CRP treatment of human aortic endothelial cells (HAECs) on eNOS interaction with caveolin-1, Hsp90, and porin. METHODS We incubated HAECs with CRP (0, 12.5, and 25 mg/L) for 1, 6, or 24 h and assessed the interaction of these proteins with eNOS by immunoprecipitation and western blotting. RESULTS CRP treatment (12.5 and 25 mg/L) of HAECs for 24 h significantly increased eNOS binding to caveolin-1 (40% and 54% increase, respectively; P < 0.05) and decreased binding to Hsp90 (33% and 66% decrease, respectively; P < 0.05). CRP (25 mg/L) also significantly decreased the binding of porin to eNOS (11% decrease, P < 0.05). Similar results were seen when HAECs were treated with CRP for 6 h. CONCLUSIONS These negative protein–protein interactions of eNOS were able to partly explain the CRP-induced decreases in the activity of this critical enzyme, which caused endothelial dysfunction.

scholarly journals Preparation and Evaluation of Silymarin-Loaded Solid Eutectic for Enhanced Anti-Inflammatory, Hepatoprotective Effect: In Vitro–In Vivo Prospect

2021 ◽  
Vol 2021 ◽  
pp. 1-13
Author(s):  
Abdulla Sherikar ◽  
Mohd Usman Mohd Siddique ◽  
Mahesh More ◽  
Sameer N. Goyal ◽  
Milan Milivojevic ◽  
...  
Keyword(s):  
Solid Dispersion ◽  
Solid Dispersions ◽  
Biological Response ◽  
Eutectic Mixture ◽  
Fold Increase ◽  
In Vitro Dissolution ◽  
Anti Inflammatory ◽  
Pvp K30

Solubility of phytochemicals is a major concern for drug delivery, permeability, and their biological response. However, advancements in the novel formulation technologies have been helping to overcome these challenges. The applications of these newer technologies are easy for commercialization and high therapeutic outcomes compared to conventional formulations. Considering these facts, the present study is aimed to prepare a silymarin-loaded eutectic mixture with three different ratios of Polyvinylpyrrolidone K30 (PVP K30) and evaluating their anti-inflammatory, and hepatoprotective effects. The preliminary phytochemical and characterization of silymarin, physical mixture, and solid dispersions suggested and successfully confirmed the formation of solid dispersion of silymarin with PVP K30. It was found that the solubility of silymarin was increased by 5-fold compared to pure silymarin. Moreover, the in vitro dissolution displayed that 83% of silymarin released within 2 h with 2.8-fold increase in dissolution rate compared to pure silymarin. Also, the in vivo study suggested that the formulation significantly reduced the carbon tetrachloride- ( 0.8620 ± 0.05034 ∗ ∗ for 1 : 3 ratio), paracetamol- ( 0.7300 ± 0.01517 ∗ ∗ for 1 : 3 ratio), and ethanol- ( 0.8100 ± 0.04037 ∗ ∗ for 1 : 3 ratio) induced hepatotoxicity in rats. Silymarin solid dispersion was prepared using homogenization methods that have prominent anti-inflammatory effect ( 0.6520 ± 0.008602 ∗ ∗ with 8.33%) in carrageenan-induced rat paw model.

Fucoidan aus Braunalgen

2021 ◽  
Vol 53 (04) ◽  
pp. 148-156
Author(s):  
Bettina Hees
Keyword(s):  
Biological Response ◽  
Biological Response Modifier ◽  
Klinische Ergebnisse ◽  
Response Modifier ◽  
First Line ◽  
Novel Food

ZusammenfassungFucoidan ist ein Polysaccharid, das in Meeresbraunalgen, vor allem der Wakame-Alge, vorkommt. Es ist in vielen Ländern Asiens Bestandteil der täglichen Ernährung mit Algen, darüber hinaus wird es in der traditionellen asiatischen Medizin zur komplementären Behandlung von Tumorerkrankungen eingesetzt. Seit Kurzem ist Fucoidan auch in der EU als „Novel Food“-Lebensmittel bzw. Nahrungsergänzung zugelassen. Fucoidane besitzen eine Vielzahl an antikanzerogenen Wirkungen, was in vitro, in vivo und in klinischen Pilotstudien nachgewiesen werden konnte: Sie reduzieren proinflammatorische Prozesse, können die Proliferation von Krebszellen unterdrücken, aktivieren die Apoptose-Signale von Krebszellen und hemmen die Bildung von vaskulären Wachstumsfaktoren (VEGF), wodurch Angiogenese und Metastasierung unterdrückt werden können. Fucoidan besitzt sowohl systemische Wirkungen – erstmalig nachgewiesen mit Hilfe der microRNA Biomarker-Diagnostik – als auch lokale Wirkungen. Als Biological Response Modifier aktiviert und verbessert Fucoidan die Immunantwort im Darm als First-Line-Abwehr von Tumorzellen und Schlüsselfaktor der Tumorbekämpfung, es wirkt zusätzlich als Booster der natürlichen Killerzellaktivität. Fucoidan kann die Nebenwirkungen von Chemo- und Strahlentherapien reduzieren und es kann die therapeutischen Effekte konventioneller Tumortherapien verbessern. Der Beitrag stellt klinische Ergebnisse zu Fucoidan beim metastasierten Kolonkarzinom sowie bei Brustkrebs vor.

Appraisal of Anti-Arthritic and Anti-Inflammatory Potential of Folkloric Medicinal Plant Peganum Harmala

2021 ◽  
Vol 21 ◽  
Author(s):  
Muhammad Furqan Akhtar ◽  
Syed Ahmad Raza ◽  
Ammara Saleem ◽  
Irfan Hamid ◽  
Mirza Muhammad Faran Ashraf Baig ◽  
...  
Keyword(s):  
Plant Extract ◽  
Protein Denaturation ◽  
In Vitro Assays ◽  
Peganum Harmala ◽  
Reactive Protein ◽  
Inflammatory Conditions ◽  
Anti Inflammatory ◽  
Dpph Scavenging

Background: Peganum harmala is traditionally used to manage rheumatoid arthritis (RA) and other inflammatory conditions. However, its use against RA has not been scientifically evaluated. The current study was designed to assess the anti-arthritic and anti-inflammatory activities of the methanolic extract of P. harmala leaves by in vitro and in vivo methods. Methods: The in vitro assays were carried out to determine the effect of plant extract on inhibition of egg albumin denaturation and human red blood cell membrane (HRBC) stabilization. Moreover, 2,2-diphenyl-1-picrylhydrazyl (DPPH) scavenging activity was performed to determine the antioxidant potential. In vivo anti-arthritic activity was performed by determining the curative effect against Complete Freund’s adjuvant (0.1 ml). The plant extract was administered to rats orally at 200, 400 and 600 mg/kg/day for 21 days. Results: The values of IC50 of plant extract in protein denaturation, stabilization of HRBC and DPPH assays were 77.54 mg/ml, 23.90 mg/ml and 58.09 µg/ml respectively. Moreover, the plant extract significantly attenuated the poly-arthritis and weight loss, anemia and paw edema. The plant extract restored the level of C-reactive protein, rheumatoid factor, alanine transaminase, aspartate transaminase and alkaline phosphatase in poly-arthritic rats. Moreover, the plant extract restored the immune organs weight in treated rats. Treatment with P. harmala also significantly subdued the oxidative stress by reinstating superoxide dismutase, reduced glutathione, catalase and malondialdehyde in poly-arthritic rats. The plant extract notably restored the prostaglandin-E2 and tumor necrosis factor (TNF)-α in the serum of poly-arthritic rats. Conclusion: It was concluded that P. harmala extract had potential antioxidant, anti-inflammatory and antiarthritic activities which primarily might be attributed to alkaloids, flavonoids and phenols.

scholarly journals C-Reactive Protein Stimulates Myeloperoxidase Release from Polymorphonuclear Cells and Monocytes: Implications for Acute Coronary Syndromes

2009 ◽  
Vol 55 (2) ◽  
pp. 361-364 ◽  
Author(s):  
Uma Singh ◽  
Sridevi Devaraj ◽  
Ishwarlal Jialal
Keyword(s):  
Plaque Rupture ◽  
Polymorphonuclear Cells ◽  
C Reactive Protein ◽  
Reactive Protein ◽  
Coronary Syndrome ◽  
Coronary Syndromes ◽  
Human Pmns ◽  
Poor Outcomes

Abstract Background: C-reactive protein (CRP), the prototypic marker of inflammation, is present in atherosclerotic plaques and appears to promote atherogenesis. Also, CRP has been localized to monocytes and tissue macrophages, which are present in the necrotic core of lesions prone to plaque rupture. Leukocyte-derived myeloperoxidase (MPO), primarily hosted in human polymorphonuclear cells (PMNs), has also been shown to be present in human atherosclerotic lesions. Because MPO and CRP concentrations are increased in acute coronary syndrome (ACS) patients and predict poor outcomes, we tested the effect of CRP on MPO release from PMNs and monocytes. Methods: We treated human PMNs and monocytes with CRP (25 and 50 mg/L for 6 h) and measured MPO release as total mass and activity in culture supernatants. We also measured nitro-tyrosinylation (NO2-Tyr) of LDL as an indicator of biological activity of CRP-mediated MPO release. Furthermore, we explored the effect of human CRP on MPO release in the rat sterile pouch model. Results: CRP treatment significantly increased release of MPO (both mass and activity) from human PMNs as well as monocytes (P < 0.05) and caused NO2-Tyr of LDL. Human CRP injection in rats resulted in increased concentrations of MPO in pouch exudates (P < 0.05), thus confirming our in vitro data. Conclusions: CRP stimulates MPO release both in vitro and in vivo, providing further cogent data for the proinflammatory effect of CRP. These results might further support the role of CRP in ACS.

scholarly journals C-Reactive Protein Induces Release of Both Endothelial Microparticles and Circulating Endothelial Cells In Vitro and In Vivo: Further Evidence of Endothelial Dysfunction

2011 ◽  
Vol 57 (12) ◽  
pp. 1757-1761 ◽  
Author(s):  
Sridevi Devaraj ◽  
Pappanaicken R Kumaresan ◽  
Ishwarlal Jialal
Keyword(s):  
Endothelial Cells ◽  
Endothelial Dysfunction ◽  
Oxidized Ldl ◽  
Circulating Endothelial Cells ◽  
Early Event ◽  
C Reactive Protein ◽  
Endothelial Microparticles ◽  
Reactive Protein

BACKGROUND Inflammation is pivotal in atherosclerosis. A key early event in atherosclerosis is endothelial dysfunction. C-reactive protein (CRP), the prototypic marker of inflammation in humans, is a risk marker for cardiovascular disease, and there is mounting evidence to support its role in atherothrombosis. CRP has been shown to promote endothelial dysfunction both in vitro and in vivo. Emerging biomarkers of endothelial dysfunction include circulating endothelial cells (CECs) and endothelial microparticles (EMPs). However, there is a paucity of data examining the effect of CRP on CEC and EMP production in vitro and in vivo. METHODS In this report, we treated human aortic endothelial cells (HAECs) with increasing concentrations of CRP (0–50 μg/mL) or boiled CRP. We counted CECs and EMPs by flow cytometry. RESULTS Although CRP treatment resulted in a significant increase in release of both CECs and EMPs, boiled CRP failed to have an effect. Pretreatment of HAECs with sepiapterin or diethylenetriamine NONOate, both of which preserve nitric oxide (NO), resulted in attenuation of CRP's effects on CECs and EMPs. CD32 and CD64 blocking antibodies but not CD16 antibody or lectin-like oxidized LDL receptor 1 small interfering RNA (LOX-1 siRNA) prevented CRP-induced production of CECs and EMPs. Furthermore, delivery of human CRP to Wistar rats compared with human serum albumin resulted in significantly increased CECs and EMPs, corroborating the in vitro findings. CONCLUSIONS We provide novel data that CRP, via NO deficiency, promotes endothelial dysfunction by inducing release of CECs and EMPs, which are biomarkers of endothelial dysfunction.

scholarly journals Flavonoids as anti-inflammatory agents

2010 ◽  
Vol 69 (3) ◽  
pp. 273-278 ◽  
Author(s):  
Mauro Serafini ◽  
Ilaria Peluso ◽  
Anna Raguzzini
Keyword(s):  
Related Factor ◽  
Plant Foods ◽  
Reactive Protein ◽  
Cellular Models ◽  
Chemical Structures ◽  
Markers Of Inflammation ◽  
Wide Range ◽  
Anti Inflammatory

Epidemiological evidence suggests that a high intake of plant foods is associated with lower risk of chronic diseases. However, the mechanism of action and the components involved in this effect have not been identified clearly. In recent years, the scientific community has agreed to focus its attention on a class of secondary metabolites extensively present in a wide range of plant foods: the flavonoids, suggested as having different biological roles. The anti-inflammatory actions of flavonoids in vitro or in cellular models involve the inhibition of the synthesis and activities of different pro-inflammatory mediators such as eicosanoids, cytokines, adhesion molecules and C-reactive protein. Molecular activities of flavonoids include inhibition of transcription factors such as NF-κB and activating protein-1 (AP-1), as well as activation of nuclear factor-erythroid 2-related factor 2 (Nrf2). However, the in vitro evidence might be somehow of limited impact due to the non-physiological concentrations utilized and to the fact that in vivo flavonoids are extensively metabolized to molecules with different chemical structures and activities compared with the ones originally present in the food. Human studies investigating the effect of flavonoids on markers of inflammation are insufficient, and are mainly focused on flavonoid-rich foods but not on pure molecules. Most of the studies lack assessment of flavonoid absorption or fail to associate an effect on inflammation with a change in circulating levels of flavonoids. Human trials with appropriate placebo and pure flavonoid molecules are needed to clarify if flavonoids represent ancillary ingredients or key molecules involved in the anti-inflammatory properties of plant foods.

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