International Journal of Molecular Sciences

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4 pages, 210 KiB

Open AccessEditorial

Signaling Pathways in Inflammation and Its Resolution: New Insights and Therapeutic Challenges

by Carla Cicala and Silvana Morello

Int. J. Mol. Sci. 2023, 24(13), 11055; https://doi.org/10.3390/ijms241311055 - 04 Jul 2023

Cited by 1 | Viewed by 910

Abstract

Tissue inflammation is a dynamic process that develops step by step, in response to an injury, to preserve tissue integrity [...] Full article

(This article belongs to the Special Issue Signaling Pathways in Inflammation and Its Resolution: New Insights and Therapeutic Challenges)

Research

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24 pages, 2642 KiB

Open AccessArticle

Imbalances in TCA, Short Fatty Acids and One-Carbon Metabolisms as Important Features of Homeostatic Disruption Evidenced by a Multi-Omics Integrative Approach of LPS-Induced Chronic Inflammation in Male Wistar Rats

by Julia Hernandez-Baixauli, Nerea Abasolo, Hector Palacios-Jordan, Elisabet Foguet-Romero, David Suñol, Mar Galofré, Antoni Caimari, Laura Baselga-Escudero, Josep M Del Bas and Miquel Mulero

Int. J. Mol. Sci. 2022, 23(5), 2563; https://doi.org/10.3390/ijms23052563 - 25 Feb 2022

Cited by 4 | Viewed by 2675

Abstract

Chronic inflammation is an important risk factor in a broad variety of physical and mental disorders leading to highly prevalent non-communicable diseases (NCDs). However, there is a need for a deeper understanding of this condition and its progression to the disease state. For [...] Read more.

Chronic inflammation is an important risk factor in a broad variety of physical and mental disorders leading to highly prevalent non-communicable diseases (NCDs). However, there is a need for a deeper understanding of this condition and its progression to the disease state. For this reason, it is important to define metabolic pathways and complementary biomarkers associated with homeostatic disruption in chronic inflammation. To achieve that, male Wistar rats were subjected to intraperitoneal and intermittent injections with saline solution or increasing lipopolysaccharide (LPS) concentrations (0.5, 5 and 7.5 mg/kg) thrice a week for 31 days. Biochemical and inflammatory parameters were measured at the end of the study. To assess the omics profile, GC-qTOF and UHPLC-qTOF were performed to evaluate plasma metabolome; ¹H-NMR was used to evaluate urine metabolome; additionally, shotgun metagenomics sequencing was carried out to characterize the cecum microbiome. The chronicity of inflammation in the study was evaluated by the monitoring of monocyte chemoattractant protein-1 (MCP-1) during the different weeks of the experimental process. At the end of the study, together with the increased levels of MCP-1, levels of interleukin-6 (IL-6), tumour necrosis factor alpha (TNF-α) and prostaglandin E2 (PGE2) along with 8-isoprostanes (an indicative of oxidative stress) were significantly increased (p-value < 0.05). The leading features implicated in the current model were tricarboxylic acid (TCA) cycle intermediates (i.e., alpha-ketoglutarate, aconitic acid, malic acid, fumaric acid and succinic acid); lipids such as specific cholesterol esters (ChoEs), lysophospholipids (LPCs) and phosphatidylcholines (PCs); and glycine, as well as N, N-dimethylglycine, which are related to one-carbon (1C) metabolism. These metabolites point towards mitochondrial metabolism through TCA cycle, β-oxidation of fatty acids and 1C metabolism as interconnected pathways that could reveal the metabolic effects of chronic inflammation induced by LPS administration. These results provide deeper knowledge concerning the impact of chronic inflammation on the disruption of metabolic homeostasis. Full article

(This article belongs to the Special Issue Signaling Pathways in Inflammation and Its Resolution: New Insights and Therapeutic Challenges)

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14 pages, 3453 KiB

Open AccessArticle

Dietary Intake of 17α-Ethinylestradiol Promotes HCC Progression in Humanized Male Mice Expressing Sex Hormone-Binding Globulin

by Sang R. Lee, Su Hee Jeong, Jun H. Heo, Seong Lae Jo, Je-Won Ko, Hyo-Jung Kwun and Eui-Ju Hong

Int. J. Mol. Sci. 2021, 22(22), 12557; https://doi.org/10.3390/ijms222212557 - 22 Nov 2021

Cited by 4 | Viewed by 2037

Abstract

Hepatocellular carcinoma (HCC) is a male-oriented malignancy; its progression is affected by sex hormones. 17α-ethinylestradiol (EE2) is a synthetic estrogen widely used as an oral contraceptive; however, it is unknown whether EE2 regulates sex hormone action in HCC. We investigated whether EE2 influences [...] Read more.

Hepatocellular carcinoma (HCC) is a male-oriented malignancy; its progression is affected by sex hormones. 17α-ethinylestradiol (EE2) is a synthetic estrogen widely used as an oral contraceptive; however, it is unknown whether EE2 regulates sex hormone action in HCC. We investigated whether EE2 influences HCC risk in male androgenic environments, using mice expressing human sex hormone-binding globulin (SHBG). Two-week-old male mice were injected with diethyl-nitrosamine (DEN, 25 mg/kg) and fed an EE2 diet for 10 weeks from 30 weeks of age. Development and characteristics of liver cancer were evaluated in 40-week-old mice via molecular and histological analyses. Although EE2 did not increase HCC progression in wild-type mice, SHBG mice exhibited remarkably higher HCC risk when fed EE2. The livers of EE2-treated SHBG mice exhibited substantially increased pro-inflammatory necrosis with high plasma levels of ALT and HMGB1, and intrahepatic injury and fibers. Additionally, increased androgen response and androgen-mediated proliferation in the livers of EE2-treated SHBG mice and EE2-exposed hepatocytes under SHBG conditions were observed. As a competitor of SHBG-androgen binding, EE2 could bind with SHBG and increase the bioavailability of androgen. Our results revealed that EE2 is a novel risk factor in androgen-dominant men, predisposing them to HCC risk. Full article

(This article belongs to the Special Issue Signaling Pathways in Inflammation and Its Resolution: New Insights and Therapeutic Challenges)

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15 pages, 6928 KiB

Open AccessArticle

Hydrogen Sulfide Reduces Ischemia and Reperfusion Injury in Neuronal Cells in a Dose- and Time-Dependent Manner

by Stefanie Scheid, Max Goeller, Wolfgang Baar, Jakob Wollborn, Hartmut Buerkle, Günther Schlunck, Wolf Lagrèze, Ulrich Goebel and Felix Ulbrich

Int. J. Mol. Sci. 2021, 22(18), 10099; https://doi.org/10.3390/ijms221810099 - 18 Sep 2021

Cited by 19 | Viewed by 2025

Abstract

Background: The ischemia-reperfusion injury (IRI) of neuronal tissue, such as the brain and retina, leads to possible cell death and loss of function. Current treatment options are limited, but preliminary observations suggest a protective effect of hydrogen sulfide (H₂S). However, the [...] Read more.

Background: The ischemia-reperfusion injury (IRI) of neuronal tissue, such as the brain and retina, leads to possible cell death and loss of function. Current treatment options are limited, but preliminary observations suggest a protective effect of hydrogen sulfide (H₂S). However, the dosage, timing, and mechanism of inhaled H₂S treatment after IRI requires further exploration. Methods: We investigated possible neuroprotective effects of inhaled H₂S by inducing retinal ischemia–reperfusion injury in rats for the duration of 1 h (120 mmHg), followed by the administration of hydrogen sulfide (H₂S) for 1 h at different time points (0, 1.5, and 3 h after the initiation of reperfusion) and at different H₂S concentrations (120, 80, and 40 ppm). We quantified the H₂S effect by conducting retinal ganglion cell counts in fluorogold-labeled animals 7 days after IRI. The retinal tissue was harvested after 24 h for molecular analysis, including qPCR and Western blotting. Apoptotic and inflammatory mediators, transcription factors, and markers for oxidative stress were investigated. Histological analyses of the retina and the detection of inflammatory cytokines in serum assays were also performed. Results: The effects of inhaled H₂S were most evident at a concentration of 80 ppm administered 1.5 h after IRI. H₂S treatment increased the expression of anti-apoptotic Bcl-2, decreased pro-apoptotic Bax expression, reduced the release of the inflammatory cytokines IL-1β and TNF-α, attenuated NF-κB p65, and enhanced Akt phosphorylation. H₂S also downregulated NOX4 and cystathionine β-synthase. Histological analyses illustrated a reduction in TNF-α in retinal ganglion cells and lower serum levels of TNF-α in H₂S-treated animals after IRI. Conclusion: After neuronal IRI, H₂S mediates neuroprotection in a time- and dose-dependent manner. The H₂S treatment modulated transcription factor NF-κB activation and reduced retinal inflammation. Full article

(This article belongs to the Special Issue Signaling Pathways in Inflammation and Its Resolution: New Insights and Therapeutic Challenges)

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25 pages, 2252 KiB

Open AccessArticle

Preclinical Development of FA5, a Novel AMP-Activated Protein Kinase (AMPK) Activator as an Innovative Drug for the Management of Bowel Inflammation

by Luca Antonioli, Carolina Pellegrini, Matteo Fornai, Laura Benvenuti, Vanessa D’Antongiovanni, Rocchina Colucci, Lorenzo Bertani, Clelia Di Salvo, Giorgia Semeghini, Concettina La Motta, Laura Giusti, Lorenzo Zallocco, Maurizio Ronci, Luca Quattrini, Francesco Angelucci, Vito Coviello, Won-Keun Oh, Quy Thi Kim Ha, Zoltan H. Németh, Gyorgy Haskó and Corrado Blandizzi Show full author list Hide full author list

Int. J. Mol. Sci. 2021, 22(12), 6325; https://doi.org/10.3390/ijms22126325 - 13 Jun 2021

Cited by 5 | Viewed by 2808

Abstract

Acadesine (ACA), a pharmacological activator of AMP-activated protein kinase (AMPK), showed a promising beneficial effect in a mouse model of colitis, indicating this drug as an alternative tool to manage IBDs. However, ACA displays some pharmacodynamic limitations precluding its therapeutical applications. Our study [...] Read more.

Acadesine (ACA), a pharmacological activator of AMP-activated protein kinase (AMPK), showed a promising beneficial effect in a mouse model of colitis, indicating this drug as an alternative tool to manage IBDs. However, ACA displays some pharmacodynamic limitations precluding its therapeutical applications. Our study was aimed at evaluating the in vitro and in vivo effects of FA-5 (a novel direct AMPK activator synthesized in our laboratories) in an experimental model of colitis in rats. A set of experiments evaluated the ability of FA5 to activate AMPK and to compare the efficacy of FA5 with ACA in an experimental model of colitis. The effects of FA-5, ACA, or dexamethasone were tested in rats with 2,4-dinitrobenzenesulfonic acid (DNBS)-induced colitis to assess systemic and tissue inflammatory parameters. In in vitro experiments, FA5 induced phosphorylation, and thus the activation, of AMPK, contextually to the activation of SIRT-1. In vivo, FA5 counteracted the increase in spleen weight, improved the colon length, ameliorated macroscopic damage score, and reduced TNF and MDA tissue levels in DNBS-treated rats. Of note, FA-5 displayed an increased anti-inflammatory efficacy as compared with ACA. The novel AMPK activator FA-5 displays an improved anti-inflammatory efficacy representing a promising pharmacological tool against bowel inflammation. Full article

(This article belongs to the Special Issue Signaling Pathways in Inflammation and Its Resolution: New Insights and Therapeutic Challenges)

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13 pages, 79440 KiB

Open AccessArticle

Management of Acute Lung Injury: Palmitoylethanolamide as a New Approach

by Alessio Filippo Peritore, Ramona D’Amico, Rosalba Siracusa, Marika Cordaro, Roberta Fusco, Enrico Gugliandolo, Tiziana Genovese, Rosalia Crupi, Rosanna Di Paola, Salvatore Cuzzocrea and Daniela Impellizzeri

Int. J. Mol. Sci. 2021, 22(11), 5533; https://doi.org/10.3390/ijms22115533 - 24 May 2021

Cited by 43 | Viewed by 3174

Abstract

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are common and devastating clinical disorders with high mortality and no specific therapy. Lipopolysaccharide (LPS) is usually used intratracheally to induce ALI in mice. The aim of this study was to examine the [...] Read more.

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are common and devastating clinical disorders with high mortality and no specific therapy. Lipopolysaccharide (LPS) is usually used intratracheally to induce ALI in mice. The aim of this study was to examine the effects of an ultramicronized preparation of palmitoylethanolamide (um-PEA) in mice subjected to LPS-induced ALI. Histopathological analysis reveals that um-PEA reduced alteration in lung after LPS intratracheal administration. Besides, um-PEA decreased wet/dry weight ratio and myeloperoxidase, a marker of neutrophils infiltration, macrophages and total immune cells number and mast cells degranulation in lung. Moreover, um-PEA could also decrease cytokines release of interleukin (IL)-6, interleukin (IL)-1β, tumor necrosis factor (TNF)-α and interleukin (IL)-18. Furthermore, um-PEA significantly inhibited the phosphorylation of nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha (IκBα) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) activation in ALI, and at the same time decreased extracellular signal-regulated kinase 1/2 (ERK1/2), c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (p38/MAPK) expression, that was increased after LPS administration. Our study suggested that um-PEA contrasted LPS-induced ALI, exerting its potential role as an adjuvant anti-inflammatory therapeutic for treating lung injury, maybe also by p38/NF-κB pathway. Full article

(This article belongs to the Special Issue Signaling Pathways in Inflammation and Its Resolution: New Insights and Therapeutic Challenges)

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Review

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16 pages, 2627 KiB

Open AccessReview

Tilting the Balance: Therapeutic Prospects of CD83 as a Checkpoint Molecule Controlling Resolution of Inflammation

by Katrin Peckert-Maier, Dmytro Royzman, Pia Langguth, Anita Marosan, Astrid Strack, Atefeh Sadeghi Shermeh, Alexander Steinkasserer, Elisabeth Zinser and Andreas B. Wild

Int. J. Mol. Sci. 2022, 23(2), 732; https://doi.org/10.3390/ijms23020732 - 10 Jan 2022

Cited by 10 | Viewed by 3093

Abstract

Chronic inflammatory diseases and transplant rejection represent major challenges for modern health care. Thus, identification of immune checkpoints that contribute to resolution of inflammation is key to developing novel therapeutic agents for those conditions. In recent years, the CD83 (cluster of differentiation 83) [...] Read more.

Chronic inflammatory diseases and transplant rejection represent major challenges for modern health care. Thus, identification of immune checkpoints that contribute to resolution of inflammation is key to developing novel therapeutic agents for those conditions. In recent years, the CD83 (cluster of differentiation 83) protein has emerged as an interesting potential candidate for such a “pro-resolution” therapy. This molecule occurs in a membrane-bound and a soluble isoform (mCD83 and sCD83, respectively), both of which are involved in resolution of inflammation. Originally described as a maturation marker on dendritic cells (DCs), mCD83 is also expressed by activated B and T cells as well as regulatory T cells (Tregs) and controls turnover of MHC II molecules in the thymus, and thereby positive selection of CD4⁺ T cells. Additionally, it serves to confine overshooting (auto-)immune responses. Consequently, animals with a conditional deletion of CD83 in DCs or regulatory T cells suffer from impaired resolution of inflammation. Pro-resolving effects of sCD83 became evident in pre-clinical autoimmune and transplantation models, where application of sCD83 reduced disease symptoms and enhanced allograft survival, respectively. Here, we summarize recent advances regarding CD83-mediated resolution of inflammatory responses, its binding partners as well as induced signaling pathways, and emphasize its therapeutic potential for future clinical trials. Full article

(This article belongs to the Special Issue Signaling Pathways in Inflammation and Its Resolution: New Insights and Therapeutic Challenges)

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26 pages, 2716 KiB

Open AccessReview

Chronic and Cycling Hypoxia: Drivers of Cancer Chronic Inflammation through HIF-1 and NF-κB Activation: A Review of the Molecular Mechanisms

by Jan Korbecki, Donata Simińska, Magdalena Gąssowska-Dobrowolska, Joanna Listos, Izabela Gutowska, Dariusz Chlubek and Irena Baranowska-Bosiacka

Int. J. Mol. Sci. 2021, 22(19), 10701; https://doi.org/10.3390/ijms221910701 - 02 Oct 2021

Cited by 119 | Viewed by 10902

Abstract

Chronic (continuous, non-interrupted) hypoxia and cycling (intermittent, transient) hypoxia are two types of hypoxia occurring in malignant tumors. They are both associated with the activation of hypoxia-inducible factor-1 (HIF-1) and nuclear factor κB (NF-κB), which induce changes in gene expression. This paper discusses [...] Read more.

Chronic (continuous, non-interrupted) hypoxia and cycling (intermittent, transient) hypoxia are two types of hypoxia occurring in malignant tumors. They are both associated with the activation of hypoxia-inducible factor-1 (HIF-1) and nuclear factor κB (NF-κB), which induce changes in gene expression. This paper discusses in detail the mechanisms of activation of these two transcription factors in chronic and cycling hypoxia and the crosstalk between both signaling pathways. In particular, it focuses on the importance of reactive oxygen species (ROS), reactive nitrogen species (RNS) together with nitric oxide synthase, acetylation of HIF-1, and the action of MAPK cascades. The paper also discusses the importance of hypoxia in the formation of chronic low-grade inflammation in cancerous tumors. Finally, we discuss the effects of cycling hypoxia on the tumor microenvironment, in particular on the expression of VEGF-A, CCL2/MCP-1, CXCL1/GRO-α, CXCL8/IL-8, and COX-2 together with PGE₂. These factors induce angiogenesis and recruit various cells into the tumor niche, including neutrophils and monocytes which, in the tumor, are transformed into tumor-associated neutrophils (TAN) and tumor-associated macrophages (TAM) that participate in tumorigenesis. Full article

(This article belongs to the Special Issue Signaling Pathways in Inflammation and Its Resolution: New Insights and Therapeutic Challenges)

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