scholarly journals Suppression of chemotherapy-induced cytokine/lipid mediator surge and ovarian cancer by a dual COX-2/sEH inhibitor

2019 ◽  
Vol 116 (5) ◽  
pp. 1698-1703 ◽  
Author(s):  
Allison Gartung ◽  
Jun Yang ◽  
Vikas P. Sukhatme ◽  
Diane R. Bielenberg ◽  
Djanira Fernandes ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Tumor Progression ◽  
Ovarian Tumor ◽  
Lipid Mediators ◽  
Lipid Mediator ◽  
Bioactive Lipids ◽  
First Line ◽  
Proinflammatory Mediators ◽  
Dual Inhibition ◽  
Cox 2

Although chemotherapy is a conventional cancer treatment, it may induce a protumorigenic microenvironment by triggering the release of proinflammatory mediators. In this study, we demonstrate that ovarian tumor cell debris generated by first-line platinum- and taxane-based chemotherapy accelerates tumor progression by stimulating a macrophage-derived “surge” of proinflammatory cytokines and bioactive lipids. Thus, targeting a single inflammatory mediator or pathway is unlikely to prevent therapy-induced tumor progression. Here, we show that combined pharmacological abrogation of the cyclooxygenase-2 (COX-2) and soluble epoxide hydrolase (sEH) pathways prevented the debris-induced surge of both cytokines and lipid mediators by macrophages. In animal models, the dual COX-2/sEH inhibitor PTUPB delayed the onset of debris-stimulated ovarian tumor growth and ascites leading to sustained survival over 120 days postinjection. Therefore, dual inhibition of COX-2/sEH may be an approach to suppress debris-stimulated ovarian tumor growth by preventing the therapy-induced surge of cytokines and lipid mediators.

scholarly journals Human and Mouse Eosinophils Differ in Their Ability to Biosynthesize Eicosanoids, Docosanoids, the Endocannabinoid 2-Arachidonoyl-glycerol and Its Congeners

Cells ◽  
2022 ◽  
Vol 11 (1) ◽  
pp. 141
Author(s):  
Anne-Sophie Archambault ◽  
Julyanne Brassard ◽  
Émilie Bernatchez ◽  
Cyril Martin ◽  
Vincenzo Di Marzo ◽  
...  
Keyword(s):  
Healthy Subjects ◽  
Biosynthetic Pathway ◽  
Lipid Mediators ◽  
Lipid Mediator ◽  
Bioactive Lipids ◽  
Eosinophilic Asthma ◽  
Asthmatic Response ◽  
Pharmacological Targets ◽  
Arachidonoyl Glycerol ◽  
Human And Mouse

High eosinophil (EOS) counts are a key feature of eosinophilic asthma. EOS notably affect asthmatic response by generating several lipid mediators. Mice have been utilized in hopes of defining new pharmacological targets to treat asthma. However, many pinpointed targets in mice did not translate into clinics, underscoring that key differences exist between the two species. In this study, we compared the ability of human (h) and mouse (m) EOS to biosynthesize key bioactive lipids derived from arachidonic acid (AA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). hEOS were isolated from the blood of healthy subjects and mild asthmatics, while mEOSs were differentiated from the bone marrow. EOSs were treated with fatty acids and lipid mediator biosynthesis assessed by LC-MS/MS. We found that hEOS biosynthesized leukotriene (LT) C4 and LTB4 in a 5:1 ratio while mEOS almost exclusively biosynthesized LTB4. The biosynthesis of the 15-lipoxygenase (LO) metabolites 15-HETE and 12-HETE also differed, with a 15-HETE:12-HETE ratio of 6.3 for hEOS and 0.727 for mEOS. EOS biosynthesized some specialized pro-resolving mediators, and the levels from mEOS were 9-times higher than those of hEOS. In contrast, hEOS produced important amounts of the endocannabinoid 2-arachidonoyl-glycerol (2-AG) and its congeners from EPA and DHA, a biosynthetic pathway that was up to ~100-fold less prominent in mEOS. Our data show that hEOS and mEOS biosynthesize the same lipid mediators but in different amounts. Compared to asthmatics, mouse models likely have an amplified involvement of LTB4 and specialized pro-resolving mediators and a diminished impact of the endocannabinoid 2-arachidonoyl-glycerol and its congeners.

scholarly journals Interleukin 3-dependent mediator release in basophils triggered by C5a.

1989 ◽  
Vol 170 (2) ◽  
pp. 467-479 ◽  
Author(s):  
Y Kurimoto ◽  
A L de Weck ◽  
C A Dahinden
Keyword(s):  
Time Course ◽  
Lipid Mediators ◽  
Mediator Release ◽  
Lipid Mediator ◽  
Cell Fractionation ◽  
Leukotriene C4 ◽  
Bioactive Lipids ◽  
Anaphylatoxin C5a ◽  
Dose Dependent

The anaphylatoxin C5a is a potent trigger for basophil degranulations, but in contrast to IgE-dependent basophil activation, it does not result in the synthesis of sulfidoleukotrienes (leukotriene C4/D4/E4). Thus, degranulation and the generation of lipid mediators are separately regulated cellular responses. Exposure of human blood basophils to the cytokine IL-3 alone does not induce the release of histamine in cells from most donors and never leads to the generation of LTC4, indicating that IL-3 is not a direct agonist for basophil mediator release. However, preincubation of basophils with IL-3 enhances the degranulation response to C5a. Most importantly, IL-3 "primes" basophils to release large amounts of leukotriene C4 after challenge with C5a (mean of 50 gp LTC4 per nanograms cellular histamine), while neither peptide alone is capable of inducing the formation of bioactive lipids. This effect is dose dependent, occurring at IL-3 concentrations considerably lower than are required to stimulate the growth of bone marrow progenitor cells. IL-3 affects the extent but not the time course of basophil degranulation, and leukotriene release of cells sequentially exposed to IL-3 and C5a occurs very rapidly concomitant with degranulation. A preincubation of the basophils with IL-3 is strictly required for C5a-induced LTC4 synthesis, but not for an enhancement of degranulation. Priming for C5a-induced lipid mediator generation occurs rapidly after exposure of the cells to IL-3, starting at 1 min and reaching maximal effects at 5 min, but this altered state of responsiveness is relatively long lasting. Cell fractionation studies indicate that the basophil is the source of lipid mediators and that IL-3 affects the basophil response directly. This study demonstrates that IL-3 is a potent modifier of effector functions of mature basophils; this is possibly of greater in vivo significance than its growth factor properties. The large amounts of LTC4 formed after triggering of IL-3-primed basophils may not only enhance but also qualitatively change the pathophysiological consequences of complement activation, and this might be important in the pathogenesis of immediate type hypersensitivity reactions, shock syndromes, and inflammation.

Quantitative profiling of inflammatory and pro-resolving lipid mediators in human adolescents and mouse plasma using UHPLC-MS/MS

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Ivan Hartling ◽  
Alessio Cremonesi ◽  
Ester Osuna ◽  
Phing-How Lou ◽  
Eliana Lucchinetti ◽  
...  
Keyword(s):  
Human Plasma ◽  
Lipid Mediators ◽  
Lipid Mediator ◽  
Prostaglandin D2 ◽  
Reference Ranges ◽  
Good Precision ◽  
Plasma Samples ◽  
Omega 3 ◽  
Bioactive Lipids ◽  
Blood Draw

Abstract Objectives Lipid mediators are bioactive lipids which help regulate inflammation. We aimed to develop an ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) method to quantify 58 pro-inflammatory and pro-resolving lipid mediators in plasma, determine preliminary reference ranges for adolescents, and investigate how total parenteral nutrition (TPN) containing omega-3 polyunsaturated fatty acid (n-3 PUFA) or n-6 PUFA based lipid emulsions influence lipid mediator concentrations in plasma. Methods Lipid mediators were extracted from plasma using SPE and measured using UHPLC-MS/MS. EDTA plasma was collected from healthy adolescents between 13 and 17 years of age to determine preliminary reference ranges and from mice given intravenous TPN for seven days containing either an n-3 PUFA or n-6 PUFA based lipid emulsion. Results We successfully quantified 43 lipid mediators in human plasma with good precision and recovery including several leukotrienes, prostaglandins, resolvins, protectins, maresins, and lipoxins. We found that the addition of methanol to human plasma after blood separation reduces post blood draw increases in 12-hydroxyeicosatetraenoic acid (12-HETE), 12-hydroxyeicosapentaenoic acid (12-HEPE), 12S-hydroxyeicosatrienoic acid (12S-HETrE), 14-hydroxydocosahexaenoic acid (14-HDHA) and thromboxane B2 (TXB2). Compared to the n-6 PUFA based TPN, the n-3 PUFA based TPN increased specialized pro-resolving mediators such as maresin 1 (MaR1), MaR2, protectin D1 (PD1), PDX, and resolvin D5 (RvD5), and decreased inflammatory lipid mediators such as leukotriene B4 (LTB4) and prostaglandin D2 (PGD2). Conclusions Our method provides an accurate and sensitive quantification of 58 lipid mediators from plasma samples, which we used to establish a preliminary reference range for lipid mediators in plasma samples of adolescents; and to show that n-3 PUFA, compared to n-6 PUFA rich TPN, leads to a less inflammatory lipid mediator profile in mice.

scholarly journals Combined therapy with COX-2 inhibitor and 20-HETE inhibitor reduces colon tumor growth and the adverse effects of ischemic stroke associated with COX-2 inhibition

2014 ◽  
Vol 307 (6) ◽  
pp. R693-R703 ◽  
Author(s):  
Yi Zhang ◽  
Md Nasrul Hoda ◽  
Xuan Zheng ◽  
Weiguo Li ◽  
Pengcheng Luo ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Tumor Growth ◽  
Combined Therapy ◽  
Tumor Therapy ◽  
Combined Treatment ◽  
Prolonged Treatment ◽  
Lipid Mediator ◽  
Colon Tumor ◽  
Stroke Outcomes ◽  
Cox 2

20-Hydroxyeicosatetraenoic acid (20-HETE), Cyp4a-derived eicosanoid, is a lipid mediator that promotes tumor growth, as well as causing detrimental effects in cerebral circulation. We determined whether concurrent inhibition of cyclooxygenase-2 (COX-2) and 20-HETE affects colon tumor growth and ischemic stroke outcomes. The expression of Cyp4a and COXs and production of 20-HETE and PGE2 were determined in murine colon carcinoma (MC38) cells. We then examined the effects of combined treatment with rofecoxib, a potent COX-2 inhibitor, and HET0016, a potent Cyp4a inhibitor, on the growth and proliferation of MC38 cells. Subsequently, we tested the effects of HET0016 plus rofecoxib in MC38 tumor and ischemic stroke models. Cyp4a and COXs are highly expressed in MC38 cells. Respectively, HET0016 and rofecoxib inhibited 20-HETE and PGE2 formation in MC38 cells. Moreover, rofecoxib combined with HET0016 had greater inhibitory effects on the growth and proliferation of MC38 cells than did rofecoxib alone. Importantly, rofecoxib combined with HET0016 provided greater inhibition on tumor growth than did rofecoxib alone in MC38 tumor-bearing mice. Prolonged treatment with rofecoxib selectively induced circulating 20-HETE levels and caused cerebrovascular damage after ischemic stroke, whereas therapy with rofecoxib and HET0016 attenuated 20-HETE levels and reduced rofecoxib-induced cerebrovascular damage and stroke outcomes during anti-tumor therapy. Thus these results demonstrate that combination therapy with rofecoxib and HET0016 provides a new treatment of colon tumor, which can not only enhance the anti-tumor efficacy of rofecoxib, but also reduce rofecoxib-induced cerebrovascular damage and stroke outcomes.

scholarly journals Emerging role of the endothelin axis in ovarian tumor progression

2005 ◽  
Vol 12 (4) ◽  
pp. 761-772 ◽  
Author(s):  
Anna Bagnato ◽  
Francesca Spinella ◽  
Laura Rosanò
Keyword(s):  
Ovarian Cancer ◽  
Protein Kinase ◽  
Tumor Growth ◽  
Tumor Progression ◽  
Ovarian Tumor ◽  
Epithelial Mesenchymal Transition ◽  
Gynecologic Cancer ◽  
Mitogen Activated Protein Kinase ◽  
Mesenchymal Transition ◽  
Multiple Tumor

Ovarian cancer is the leading cause of gynecologic cancer-related deaths. The endothelin (ET) axis, which includes ET-1, ET-2, ET-3, and the ET receptors, ETAR and ETBR, represents a novel target in tumor treatment. ET-1 may directly contribute to tumor growth and indirectly modulate tumor–host interactions in various tumors such as prostatic, ovarian, renal, pulmonary, colorectal, cervical, breast carcinoma, Kaposi’s sarcoma, brain tumors and melanoma. Extensive experimental evidence links ETAR overexpression with tumor progression in ovarian cancer. ETAR engagement can in fact activate multiple signal transduction pathways including protein kinase C, phosphati-dylinositol 3-kinase, mitogen-activated protein kinase and transactivate epidermal growth factor receptor, which play a role in ovarian tumor growth and invasion. The effects of ETAR signaling are wide ranging and involve both cancer cells and their surrounding stroma, including the vasculature. Upon being activated, the ETAR mediates multiple tumor-promoting activities, including enhanced cell proliferation, escape from apoptosis, angiogenesis, epithelial–mesenchymal transition and increased motility and invasiveness. These findings indicate that activation of ETAR by ET-1 is a key mechanism in the cellular signaling network promoting ovarian cancer growth and progression. The predominant role played by ETAR in cancer has led to the development of small molecules that antagonize the binding of ET-1 to ETAR. The emerging preclinical data presented here provide a rationale for the clinical evaluation of these molecules in which targeting the related signaling cascade via ETAR blockade may be advantageous in the treatment of advanced stage ovarian carcinoma.

scholarly journals Gallic Acid-L-Leucine Conjugate Protects Mice against LPS-Induced Inflammation and Sepsis via Correcting Proinflammatory Lipid Mediator Profiles and Oxidative Stress

2018 ◽  
Vol 2018 ◽  
pp. 1-14 ◽  
Author(s):  
Yuanyuan Cheng ◽  
Xuechen Li ◽  
Hung-Fat Tse ◽  
Jianhui Rong
Keyword(s):  
Gallic Acid ◽  
Map Kinases ◽  
Nuclear Translocation ◽  
Endotoxic Shock ◽  
Lipid Mediators ◽  
Lipid Mediator ◽  
No Production ◽  
Dependent Manner ◽  
Cox 2 ◽  
Anti Inflammatory

The pathology of endotoxin LPS-induced sepsis is hallmarked by aberrant production of proinflammatory lipid mediators and nitric oxide (NO). The aim of the present study was to determine whether the new product gallic acid-L-leucine (GAL) conjugate could ameliorate the LPS-induced dysregulation of arachidonic acid metabolism and NO production. We first investigated the effects of GAL conjugate on the expression of proinflammatory enzymes and the production of proinflammatory NO and lipid mediators in mouse macrophage cell line RAW264.7, primary peritoneal macrophages, and mouse model. Western blot analyses revealed that GAL attenuated LPS-induced expression of iNOS, COX-2, and 5-LOX in a concentration-dependent manner. Consistently, probing NO-mediated fluorescence revealed that GAL antagonized the stimulatory effect of LPS on iNOS activity. By profiling of lipid mediators with ESI-MS-based lipidomics, we found that GAL suppressed LPS-induced overproduction of prostaglandin E2, prostaglandin F2, leukotriene B4, and thromboxane B2. We further discovered that GAL might exhibit anti-inflammatory activities by the following mechanisms: (1) suppressing LPS-induced activation of MAP kinases (i.e., ERK1/2, JNK, and p38); (2) reducing the production of reactive oxygen species (ROS); and (3) preventing LPS-induced nuclear translocation of transcription factors NF-κB and AP-1. Consequently, GAL significantly decreased the levels of COX-2 and iNOS expression and the plasma levels of proinflammatory lipid mediators in LPS-treated mice. GAL pretreatment enhanced the survival of mice against LPS-induced endotoxic shock. Taken together, our results suggest that GAL may be a potential anti-inflammatory drug for the treatment of endotoxemia and sepsis.

scholarly journals Suppression of Chemotherapy‐induced Cytokine/Eicosanoid Storm and Ovarian Tumor Growth by a Dual COX‐2/sEH Inhibitor

2018 ◽  
Vol 32 (S1) ◽  
Author(s):  
Allison Gartung ◽  
Jun Yang ◽  
Djanira Fernandes ◽  
Jaimie Chang ◽  
Sung Hee Hwang ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Ovarian Tumor ◽  
Cox 2

Expressions of cyclooxygenase-2 (COX-2) and prostaglandin E receptors (EPs) in gallbladder carcinoma (GBca)-association with tumor progression

2001 ◽  
Vol 120 (5) ◽  
pp. A573-A573
Author(s):  
J SHODA ◽  
T ASANO ◽  
T KAWAMOTO ◽  
Y MATSUZAKI ◽  
N TANAKA ◽  
...  
Keyword(s):  
Tumor Progression ◽  
Gallbladder Carcinoma ◽  
Cyclooxygenase 2 ◽  
Prostaglandin E ◽  
Cox 2

Simulated microgravity model of ovarian tumor growth

1993 ◽  
Author(s):  
Jeanne Becker ◽  
Thomas Goodwin ◽  
Tacey Prewett ◽  
Glenn Spaulding
Keyword(s):  
Tumor Growth ◽  
Ovarian Tumor ◽  
Simulated Microgravity

scholarly journals Intrabodies targeting human papillomavirus 16 E6 and E7 oncoproteins for therapy of established HPV-associated tumors

2021 ◽  
Vol 40 (1) ◽  
Author(s):  
Francesca Paolini ◽  
Carla Amici ◽  
Mariantonia Carosi ◽  
Claudia Bonomo ◽  
Paola Di Bonito ◽  
...  
Keyword(s):  
Human Papillomavirus ◽  
Antitumor Activity ◽  
Tumor Growth ◽  
Tumor Progression ◽  
Cellular Transformation ◽  
Neoplastic Progression ◽  
Single Chain ◽  
Hpv16 E6 ◽  
Associated Lesions ◽  
E6 And E7

Abstract Background The oncogenic activity of the high risk human papillomavirus type 16 (HPV16) is fully dependent on the E6 and E7 viral oncoproteins produced during viral infection. The oncoproteins interfere with cellular homeostasis by promoting proliferation, inhibiting apoptosis and blocking epithelial differentiation, driving the infected cells towards neoplastic progression. The causal relationship between expression of E6/E7 and cellular transformation allows inhibiting the oncogenic process by hindering the activity of the two oncoproteins. We previously developed and characterized some antibodies in single-chain format (scFvs) against the HPV16 E6 and E7 proteins, and demonstrated both in vitro and in vivo their antitumor activity consisting of protective efficacy against tumor progression of HPV16-positive cells. Methods Envisioning clinical application of the best characterized anti-HPV16 E6 and –HPV16 E7 scFvs, we verified their activity in the therapeutic setting, on already implanted tumors. Recombinant plasmids expressing the anti-HPV16 E6 scFvI7 with nuclear targeting sequence, or the anti-HPV16 E7 scFv43M2 with endoplasmic reticulum targeting sequence were delivered by injection followed by electroporation to three different preclinical models using C57/BL6 mice, and their effect on tumor growth was investigated. In the first model, the HPV16+ TC-1 Luc cells were used to implant tumors in mice, and tumor growth was measured by luciferase activity; in the second model, a fourfold number of TC-1 cells was used to obtain more aggressively growing tumors; in the third model, the HPV16+ C3 cells where used to rise tumors in mice. To highlight the scFv possible mechanism of action, H&E and caspase-3 staining of tumor section were performed. Results We showed that both the anti-HPV16 E6 and HPV16 E7 scFvs tested were efficacious in delaying tumor progression in the three experimental models and that their antitumor activity seems to rely on driving tumor cells towards the apoptotic pathway. Conclusion Based on our study, two scFvs have been identified that could represent a safe and effective treatment for the therapy of HPV16-associated lesions. The mechanism underlying the scFv effectiveness appears to be leading cells towards death by apoptosis. Furthermore, the validity of electroporation, a methodology allowed for human treatment, to deliver scFvs to tumors was confirmed.

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