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Journal ArticleDOI

Functional N-Formyl Peptide Receptor 2 (FPR2) Antagonists Based on the Ureidopropanamide Scaffold Have Potential To Protect Against Inflammation-Associated Oxidative Stress.

22 Nov 2017-ChemMedChem (John Wiley & Sons, Ltd)-Vol. 12, Iss: 22, pp 1839-1847
TL;DR: A new series of ureidopropanamide derivatives were designed with the goal of converting functional activity from agonism into antagonism and to develop new FPR2 antagonists, and showed that they decreased the production of reactive oxygen species in mouse microglial N9 cells after stimulation with lipopolysaccharide.
Abstract: Formyl peptide receptor-2 (FPR2) is a G protein-coupled receptor belonging to the N-formyl peptide receptor (FPR) family that plays critical roles in peripheral and brain inflammatory responses. FPR2 has been proposed as a target for the development of drugs that could facilitate the resolution of chronic inflammatory reactions by enhancing endogenous anti-inflammation systems. Starting from the structure of the FPR2 agonists (R)- and (S)-4 and 2, we designed a new series of ureidopropanamide derivatives with the goal of converting functional activity from agonism to antagonism and to develop new FPR2 antagonists. Although none of the compounds behaved as antagonist, some of the compounds were able to induce receptor desensitization, thus functionally behaving as antagonists. Evaluation of these compounds in an in vitro model of neuroinflammation showed that they reduced reactive oxygen species (ROS) production in mouse microglial N9 cells after stimulation with lipopolysaccharide (LPS). These FPR2 ligands may protect cells from damage due to inflammation-associated oxidative stress.
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Journal ArticleDOI
TL;DR: A comprehensive overview of recent progress made in the development of FPR2/ALX agonists which promote resolution and tissue regeneration can be found in this article, where the focus of the review is to provide a comprehensive overview.

28 citations

Journal ArticleDOI
TL;DR: A significant role is disclosed in the oxidative stress-induced apoptosis of NP cells, which could be involved in the primary pathogenesis of IDD, and it is revealed that allicin could be a promising therapeutic approach against AOPP-mediated oxidative stress during IDD progression.
Abstract: Intervertebral disc degeneration (IDD) is one of the most common chronic degenerative musculoskeletal disorders. Oxidative stress-induced apoptosis of the nucleus pulposus (NP) cells plays a key role during IDD progression. Advanced oxidation protein products (AOPP), novel biomarkers of oxidative stress, have been reported to function in various diseases due to their potential for disrupting the redox balance. The current study is aimed at investigating the function of AOPP in the oxidative stress-induced apoptosis of human NP cells and the alleviative effects of allicin during this process which was known for its antioxidant properties. AOPP were demonstrated to hamper the viability and proliferation of NP cells in a time- and concentration-dependent manner and cause cell apoptosis markedly. High levels of reactive oxygen species (ROS) and lipid peroxidation product malondialdehyde (MDA) were detected in NP cells after AOPP stimulation, which resulted in depolarized mitochondrial transmembrane potential (MTP). Correspondingly, higher levels of AOPP were discovered in the human degenerative intervertebral discs (IVD). It was also found that allicin could protect NP cells against AOPP-mediated oxidative stress and mitochondrial dysfunction via suppressing the p38-MAPK pathway. These results disclosed a significant role of AOPP in the oxidative stress-induced apoptosis of NP cells, which could be involved in the primary pathogenesis of IDD. It was also revealed that allicin could be a promising therapeutic approach against AOPP-mediated oxidative stress during IDD progression.

22 citations

Journal ArticleDOI
TL;DR: In this paper, the authors investigated the effects of Fpr2 activation in the treatment of scleroderma fibrosis and found that intradermal administration of WKYMVm, a G protein-coupled receptor that modulates inflammation and host defense by regulating the activation of inflammatory cells, such as macrophages.
Abstract: Systemic sclerosis is a profibrotic autoimmune disease mediated by the dysregulation of extracellular matrix synthesis. Formyl peptide receptor 2 (Fpr2) is a G protein-coupled receptor that modulates inflammation and host defense by regulating the activation of inflammatory cells, such as macrophages. However, the role of Fpr2 in the development and therapy of scleroderma is still unclear. The present study was conducted to investigate the effects of Fpr2 activation in the treatment of scleroderma fibrosis. We found that intradermal administration of WKYMVm, an Fpr2-specific agonist, alleviated bleomycin-induced scleroderma fibrosis in mice and decreased dermal thickness in scleroderma skin. WKYMVm-treated scleroderma skin tissues displayed reduced numbers of myofibroblasts expressing α-smooth muscle actin, Vimentin, and phosphorylated SMAD3. WKYMVm treatment attenuated macrophage infiltration in scleroderma skin and reduced the number of M2 macrophages. The therapeutic effects of WKYMVm in scleroderma-associated fibrosis and inflammation were completely abrogated in Fpr2 knockout mice. Moreover, WKYMVm treatment reduced the serum levels of inflammatory cytokines, such as tumor necrosis factor-α, and interferon-γ, in the scleroderma model of wild-type mice but not in Fpr2 knockout mice. These results suggest that WKYMVm-induced activation of Fpr2 leads to alleviation of fibrosis by stimulating immune resolution in systemic sclerosis.

19 citations


Cites background from "Functional N-Formyl Peptide Recepto..."

  • ...derivatives, induced FPR2 internalization and desensitization (25, 31)....

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Journal ArticleDOI
TL;DR: In this paper, a prognostic signature composed of 13 immune-related genes (IRGs) was constructed by comprehensively computational analyses of hundreds of head and neck squamous cell carcinoma (HNSC) samples.
Abstract: Immunotherapy has become a promising therapeutic option for Head and neck squamous cell carcinoma (HNSC) However, only a small percentage of patients could benefit from it, and the overall prognosis was far from satisfactory In this study, by comprehensively computational analyses of hundreds of HNSC samples, a prognostic signature composed of 13 immune-related genes (IRGs) was constructed The results of the analyses in multiple datasets indicated that our signature had high predictive accuracy and could serve as an independent prognostic predictor Based on this signature and multiple clinical variables, we also established a prognostic nomogram to quantitatively predict the survival risk of individual patients Moreover, this signature could accurately predict survival, reflect the immune microenvironment, and predict immunotherapy efficacy among HNSC patients Two potential drugs (doxorubicin and daunorubicin) were also identified via Connectivity Map and molecular docking, which could be used for HNSC combination therapy Taken together, we developed and validated a robust IRG-based prognostic signature to monitor the prognosis of HNSC, which could provide a solid foundation for individualized cancer immunotherapy

8 citations

Journal ArticleDOI
TL;DR: In this article, homology modelling, molecular docking and pharmacophore studies were deployed to assist the rationalization of the structure-activity relationships of known formyl peptide receptor 2 (FPR2) agonists.

8 citations

References
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Journal ArticleDOI
TL;DR: It is reported that lipidomic analysis of exudates obtained in the resolution phase from mice treated with ASA and docosahexaenoic acid produce a novel family of bioactive 17R-hydroxy-containing di- and tri-Hydroxy-docosanoids termed resolvins.
Abstract: Aspirin (ASA) is unique among current therapies because it acetylates cyclooxygenase (COX)-2 enabling the biosynthesis of R- containing precursors of endogenous antiinflammatory mediators. Here, we report that lipidomic analysis of exudates obtained in the resolution phase from mice treated with ASA and docosahexaenoic acid (DHA) (C22:6) produce a novel family of bioactive 17 R -hydroxy-containing di- and tri-hydroxy-docosanoids termed resolvins. Murine brain treated with aspirin produced endogenous 17 R -hydroxydocosahexaenoic acid as did human microglial cells. Human COX-2 converted DHA to 13-hydroxy-DHA that switched with ASA to 17 R -HDHA that also proved a major route in hypoxic endothelial cells. Human neutrophils transformed COX-2-ASA‐derived 17 R -hydroxy-DHA into two sets of novel diand trihydroxy products; one initiated via oxygenation at carbon 7 and the other at carbon 4. These compounds inhibited (IC 50 � 50 pM) microglial cell cytokine expression and in vivo dermal inflammation and peritonitis at ng doses, reducing 40‐80% leukocytic exudates. These results indicate that exudates, vascular, leukocytes and neural cells treated with aspirin convert DHA to novel 17 R -hydroxy series of docosanoids that are potent regulators. These biosynthetic pathways utilize omega-3 DHA and EPA during multicellular events in resolution to produce a family of protective compounds, i.e., resolvins, that enhance proresolution status.

1,608 citations

Journal ArticleDOI
TL;DR: The molecular mechanisms by which hydrogen peroxide is sensed and the increasing evidence that antioxidant enzymes play multiple, key roles as sensors and regulators of signal transduction in response to hydrogen peroxy are discussed.

1,464 citations

Journal ArticleDOI
Richard M. Ransohoff1
19 Aug 2016-Science
TL;DR: Observations indicate that therapies targeting glial cells might provide benefit for those afflicted by neurodegenerative disorders, because the environment is affected during disease in a cascade of processes collectively termed neuroinflammation.
Abstract: Neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, and frontotemporal lobar dementia are among the most pressing problems of developed societies with aging populations. Neurons carry out essential functions such as signal transmission and network integration in the central nervous system and are the main targets of neurodegenerative disease. In this Review, I address how the neuron’s environment also contributes to neurodegeneration. Maintaining an optimal milieu for neuronal function rests with supportive cells termed glia and the blood-brain barrier. Accumulating evidence suggests that neurodegeneration occurs in part because the environment is affected during disease in a cascade of processes collectively termed neuroinflammation. These observations indicate that therapies targeting glial cells might provide benefit for those afflicted by neurodegenerative disorders.

1,291 citations

Journal ArticleDOI
TL;DR: A consensus report was needed that addresses the rapid progress in this emerging field and details how the specific study of resolution of acute inflammation provides leads for novel anti‐inflammatory therapeutics, as well as defines the terms and key components of interest in the resolution process within tissues as appreciated today.
Abstract: A recent focus meeting on Controlling Acute Inflammation was held in London, April 27-28, 2006, organized by D.W. Gilroy and S.D. Brain for the British Pharmacology Society. We concluded at the meeting that a consensus report was needed that addresses the rapid progress in this emerging field and details how the specific study of resolution of acute inflammation provides leads for novel anti-inflammatory therapeutics, as well as defines the terms and key components of interest in the resolution process within tissues as appreciated today. The inflammatory response protects the body against infection and injury but can itself become dysregulated with deleterious consequences to the host. It is now evident that endogenous biochemical pathways activated during defense reactions can counter-regulate inflammation and promote resolution. Hence, resolution is an active rather than a passive process, as once believed, which now promises novel approaches for the treatment of inflammation-associated diseases based on endogenous agonists of resolution.

1,037 citations

Journal ArticleDOI
TL;DR: An important and specific role of GRKs and beta arrestins in regulating physiological responsiveness to psychostimulants and morphine suggests potential involvement of these molecules in certain brain disorders, such as addiction, Parkinson's disease, mood disorders, and schizophrenia.
Abstract: ▪ Abstract G protein–coupled receptors (GPCRs) have proven to be the most highly favorable class of drug targets in modern pharmacology Over 90% of nonsensory GPCRs are expressed in the brain, where they play important roles in numerous neuronal functions GPCRs can be desensitized following activation by agonists by becoming phosphorylated by members of the family of G protein–coupled receptor kinases (GRKs) Phosphorylated receptors are then bound by arrestins, which prevent further stimulation of G proteins and downstream signaling pathways Discussed in this review are recent progress in understanding basics of GPCR desensitization, novel functional roles, patterns of brain expression, and receptor specificity of GRKs and βarrestins in major brain functions In particular, screening of genetically modified mice lacking individual GRKs or βarrestins for alterations in behavioral and biochemical responses to cocaine and morphine has revealed a functional specificity in dopamine and μ-opioid receptor re

834 citations