scholarly journals The Novel H4R Antagonist 1-[(5-Chloro-2,3-Dihydro-1-Benzofuran-2-Yl)Methyl]-4-Methyl-Piperazine (LINS01007) Attenuates Several Symptoms in Murine Allergic Asthma

2020 ◽  
Vol 54 (6) ◽  
pp. 1163-1176
Keyword(s):  
Lung Tissue ◽  
Inflammatory Diseases ◽  
Lavage Fluid ◽  
Wall Thickening ◽  
Histamine H4 Receptor ◽  
Asthma Model ◽  
Allergic Lung Inflammation ◽  
Inflammatory Processes ◽  
Cox 2 ◽  
H4 Receptor

BACKGROUND/AIMS: Histamine is an important chemical transmitter involved in inflammatory processes, including asthma and other chronic inflammatory diseases. Its inflammatory effects involve mainly the histamine H4 receptor (H4R), whose role in several studies has already been demonstrated. Our group have explored the effects of 1-[(2,3-dihydro-1-benzofuran-2-yl)methyl]piperazines as antagonists of H4R, and herein the compounds LINS01005 and LINS01007 were studied with more details, considering the different affinity profile on H4R and the anti-inflammatory potential of both compounds. METHODS: We carried out a more focused evaluation of the modulatory effects of LINS01005 and LINS01007 in a murine asthma model. The compounds were given i.p. (1-7 mg/kg) to ovalbumin sensitized BALB/c male mice (12 weeks old) 30 min before the antigen challenging, and after 24 h the cell analysis from the bronchoalveolar lavage fluid (BALF) was performed. The lung tissue was used for evaluation by western blot (COX-2, 5-LO, NF-κB and STAT3 expressions) and histological analysis. RESULTS: Treatment with the more potent H4R antagonist LINS01007 significantly decreased the total cell count and eosinophils in BALF at lower doses when compared to LINS01005. The expression of COX-2, 5-LO, NF-κB and STAT3 in lung tissue was significantly reduced after treatment with LINS01007. Morphophysiological changes such as mucus and collagen production and airway wall thickening were significantly reduced after treatment with LINS01007. CONCLUSION: These results show important down regulatory effect of novel H4R antagonist (LINS01007) on allergic lung inflammation.

Targeting the Histamine H4 Receptor: Future Drugs for Inflammatory Diseases

2018 ◽  
Vol 22 (17) ◽  
pp. 1663-1672 ◽  
Author(s):  
Michelle Fidelis Correa ◽  
Joao Paulo dos Santos Fernandes
Keyword(s):  
Inflammatory Diseases ◽  
Histamine H4 Receptor ◽  
H4 Receptor

scholarly journals The Function of the Histamine H4 Receptor in Inflammatory and Inflammation-Associated Diseases of the Gut

2021 ◽  
Vol 22 (11) ◽  
pp. 6116
Author(s):  
Bastian Schirmer ◽  
Detlef Neumann
Keyword(s):  
Inflammatory Diseases ◽  
Allergic Inflammation ◽  
Histamine H4 Receptor ◽  
Ongoing Research ◽  
Inflammatory Reactions ◽  
Beneficial Effects ◽  
Associated Diseases ◽  
Physiological Processes ◽  
H4 Receptor ◽  
Deficient Mice

Histamine is a pleiotropic mediator involved in a broad spectrum of (patho)-physiological processes, one of which is the regulation of inflammation. Compounds acting on three out of the four known histamine receptors are approved for clinical use. These approved compounds comprise histamine H1-receptor (H1R) antagonists, which are used to control allergic inflammation, antagonists at H2R, which therapeutically decrease gastric acid release, and an antagonist at H3R, which is indicated to treat narcolepsy. Ligands at H4R are still being tested pre-clinically and in clinical trials of inflammatory diseases, including rheumatoid arthritis, asthma, dermatitis, and psoriasis. These trials, however, documented only moderate beneficial effects of H4R ligands so far. Nevertheless, pre-clinically, H4R still is subject of ongoing research, analyzing various inflammatory, allergic, and autoimmune diseases. During inflammatory reactions in gut tissues, histamine concentrations rise in affected areas, indicating its possible biological effect. Indeed, in histamine-deficient mice experimentally induced inflammation of the gut is reduced in comparison to that in histamine-competent mice. However, antagonists at H1R, H2R, and H3R do not provide an effect on inflammation, supporting the idea that H4R is responsible for the histamine effects. In the present review, we discuss the involvement of histamine and H4R in inflammatory and inflammation-associated diseases of the gut.

Rgx365, a Rare Protopanaxatriol-Type Ginsenoside Fraction from Black Ginseng, Suppresses Inflammatory Gene iNOS via the Iinhibition of p-STAT-1 and NF-κB

2020 ◽  
Vol 48 (05) ◽  
pp. 1091-1102
Author(s):  
So Yeon Jeong ◽  
Ji-Eun Kim ◽  
Gyu-Yong Song ◽  
Jong-Sup Bae
Keyword(s):  
Lung Tissue ◽  
Lavage Fluid ◽  
Heme Oxygenase 1 ◽  
Inos Protein ◽  
Protein Levels ◽  
Rna Transfection ◽  
Inos Protein Expression ◽  
Black Ginseng ◽  
Cox 2 ◽  
Human Pulmonary Artery

Black ginseng (BG), which is ginseng that has been steamed and dried nine times, and its main protopanaxatriol-type ginsenosides Rg4, Rg6, Rh4, and Rg2 have been reported to exhibit various forms of biological activity, including antiseptic, antidiabetic, wound-healing, immune-stimulatory, and anti-oxidant activity. The aim of the this study was to examine the effects of [Formula: see text] (a rare protopanaxatriol-type ginsenoside fraction; Rg2, Rg4, Rg6, Rh1, and Rh4) on heme oxygenase-1 (HO-1) induction and on the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX-)2 in lipopolysaccharide (LPS)-activated human pulmonary artery endothelial cells (HPAECs). [Formula: see text] was tested to determine its effect on iNOS protein expression and inflammatory markers (interleukin [IL]-1[Formula: see text] and tumor necrosis factor [TNF]-[Formula: see text] in the lung tissue of LPS-treated mice. The results showed that [Formula: see text] induced the expression of HO-1, reduced LPS-activated NF-[Formula: see text]B-luciferase activity, and inhibited iNOS/NO and COX-2/PGE2, which contributed to the inhibition of STAT-1 phosphorylation. In particular, [Formula: see text] induced the translocation of Nrf2 from the cytosol to the nucleus by increasing Nrf2-ARE activity and decreased IL-1[Formula: see text] production in LPS-activated HPAECs. This reduction in iNOS/NO expression due to [Formula: see text] was reversed by siHO-1 RNA transfection. In LPS-treated mice, [Formula: see text] significantly reduced lung tissue iNOS protein levels and TNF-[Formula: see text] levels in the bronchoalveolar lavage fluid. In conclusion, these findings indicate that [Formula: see text] has a critical anti-inflammatory effect due to its ability to regulate iNOS via the inhibition of p-STAT-1 and NF-[Formula: see text]B, and thus it may be suitable for the treatment of inflammatory disease.

scholarly journals Maslinic Acid Ameliorates Inflammation via the Downregulation of NF-κB and STAT-1

Antioxidants ◽  
2020 ◽  
Vol 9 (2) ◽  
pp. 106 ◽  
Author(s):  
Wonhwa Lee ◽  
Jaehong Kim ◽  
Eui Kyun Park ◽  
Jong-Sup Bae
Keyword(s):  
Nuclear Translocation ◽  
Inflammatory Diseases ◽  
Umbilical Vein ◽  
Lavage Fluid ◽  
Maslinic Acid ◽  
Tnf Α ◽  
Cox 2 ◽  
Umbilical Vein Endothelial Cells ◽  
Oxide Synthase ◽  
Necrosis Factor

Maslinic acid (MA), a natural compound of the triterpenoid group derived from olive, prevents the generation of pro-inflammatory cytokines and oxidative stress. In human umbilical vein endothelial cells (HUVECs) treated with lipopolysaccharide (LPS), we characterized the effects of MA on the regulation of heme oxygenase (HO)-1, cyclooxygenase (COX-)2, and inducible nitric oxide synthase (iNOS). MA was tested in the lung tissues of LPS-treated mice, to determine its effect on levels of iNOS expression and representative inflammatory mediators such as interleukin (IL)-1α and tumor necrosis factor (TNF)-α. We show that MA induced the expression of HO-1, reduced LPS-induced NF-κB-luciferase activity, and inhibited iNOS/NO and COX-2/PGE2, resulting in the downregulation of STAT-1 phosphorylation. Furthermore, our data show that MA induced the nuclear translocation of Nrf2, increased the binding of Nrf2 to ARE, and decreased IL-1α production in LPS-treated HUVECs. The MA-induced reduction in iNOS/NO expression was reversed by RNAi suppression of HO-1. In mice treated with LPS, MA significantly downregulated levels of iNOS in lung tissue and TNF-α in the bronchoalveolar lavage fluid. Taken together, our findings indicate that MA exerts a critical anti-inflammatory effect by modulating iNOS via the downregulation of NF-κB and p-STAT-1. Thus, we propose that MA may be an ideal substance to treat inflammatory diseases.

Cloning and characterization of dominant negative splice variants of the human histamine H4 receptor

2008 ◽  
Vol 414 (1) ◽  
pp. 121-131 ◽  
Author(s):  
Richard M. van Rijn ◽  
André van Marle ◽  
Paul L. Chazot ◽  
Ellen Langemeijer ◽  
Yongjun Qin ◽  
...  
Keyword(s):  
Mast Cells ◽  
Mammalian Cells ◽  
Splice Variants ◽  
Inflammatory Diseases ◽  
Dominant Negative ◽  
Full Length ◽  
Dominant Negative Effect ◽  
Histamine H4 Receptor ◽  
Negative Effect ◽  
H4 Receptor

The H4R (histamine H4 receptor) is the latest identified member of the histamine receptor subfamily of GPCRs (G-protein-coupled receptors) with potential functional implications in inflammatory diseases and cancer. The H4R is primarily expressed in eosinophils and mast cells and has the highest homology with the H3R. The occurrence of at least twenty different hH3R (human H3R) isoforms led us to investigate the possible existence of H4R splice variants. In the present paper, we report on the cloning of the first two alternatively spliced H4R isoforms from CD34+ cord blood-cell-derived eosinophils and mast cells. These H4R splice variants are localized predominantly intracellularly when expressed recombinantly in mammalian cells. We failed to detect any ligand binding, H4R–ligand induced signalling or constitutive activity for these H4R splice variants. However, when co-expressed with full-length H4R [H4R(390) (H4R isoform of 390 amino acids)], the H4R splice variants have a dominant negative effect on the surface expression of H4R(390). We detected H4R(390)–H4R splice varianthetero-oligomers by employing both biochemical (immunoprecipitation and cell-surface labelling) and biophysical [time-resolved FRET (fluorescence resonance energy transfer)] techniques. mRNAs encoding the H4R splice variants were detected in various cell types and expressed at similar levels to the full-length H4R(390) mRNA in, for example, pre-monocytes. We conclude that the H4R splice variants described here have a dominant negative effect on H4R(390) functionality, as they are able to retain H4R(390) intracellularly and inactivate a population of H4R(390), presumably via hetero-oligomerization.

scholarly journals Chronic pharmacological antagonism of murine GM-CSF-R-alpha does not replicate the Pulmonary Alveolar Proteinosis phenotype but does alter lung surfactant turnover

2021 ◽  
Author(s):  
Dominic J Corkill ◽  
Alan N Hunt ◽  
Mary Jane Hinrichs ◽  
Nicholas White ◽  
Marlon Rebelatto ◽  
...  
Keyword(s):  
Lung Tissue ◽  
Pulmonary Alveolar Proteinosis ◽  
Inflammatory Diseases ◽  
Lung Surfactant ◽  
Lavage Fluid ◽  
Α Subunit ◽  
Knock Out ◽  
Gm Csf ◽  
Significant Impairment ◽  
Alveolar Proteinosis

Granulocyte macrophage colony stimulating factor (GM-CSF) is a key participant in, and a clinical target for, the treatment of inflammatory diseases including rheumatoid arthritis (RA).  Therapeutic inhibition of GM-CSF signalling using monoclonal antibodies to the α-subunit of the GM-CSF receptor (GMCSFRα) has shown clear benefit in patients with RA, giant cell arteritis (GCA)  and some efficacy in severe SARS-CoV-2 infection.  However, GM-CSF autoantibodies are associated with the development of pulmonary alveolar proteinosis (PAP), a rare lung disease characterised by alveolar macrophage (AM) dysfunction and the accumulation of surfactant lipids.  We assessed how the anti-GMCSFRα approach might impact surfactant turnover in the airway.  Female C57Bl/6J mice received a mouse-GMCSFRα blocking antibody (CAM-3003) twice per week for up to 24 weeks. A parallel, comparator cohort of the mouse PAP model, GMCSFRβ knock-out (KO), was maintained up to 16 weeks.  We assessed lung tissue histopathology alongside lung phosphatidylcholine (PC) metabolism using stable isotope lipidomics.  GMCSFRβ KO mice reproduced the histopathological and biochemical features of PAP, accumulating surfactant PC in both broncho-alveolar lavage fluid (BALF) and lavaged lung tissue.  The incorporation pattern of methyl-D9-choline showed impaired catabolism and not enhanced synthesis.  In contrast, chronic supra-pharmacological CAM-3003 exposure (100mg/kg) over 24 weeks did not elicit a histopathological PAP phenotype despite some changes in lung PC catabolism.  Lack of significant impairment of AM catabolic function supports clinical observations that therapeutic antibodies to this pathway have not been associated with PAP in clinical trials.

scholarly journals Therapeutic Efficacy of Curcumin Enhanced by Microscale Discoidal Polymeric Particles in a Murine Asthma Model

Pharmaceutics ◽  
2020 ◽  
Vol 12 (8) ◽  
pp. 739 ◽  
Author(s):  
Jun Young Park ◽  
Ga Eul Chu ◽  
Sanghyo Park ◽  
Chaewon Park ◽  
Susmita Aryal ◽  
...  
Keyword(s):  
Therapeutic Efficacy ◽  
Ex Vivo ◽  
Inflammatory Cells ◽  
Lavage Fluid ◽  
Control Group ◽  
Wall Thickening ◽  
Cell Hyperplasia ◽  
Asthma Model ◽  
Polymeric Particles ◽  
Murine Asthma Model

Curcumin is considered a potential anti-asthmatic agent owing to its anti-inflammatory properties. The objective of the present study was to prepare curcumin-containing poly(lactic-co-glycolic acid)-based microscale discoidal polymeric particles (Cur-PLGA-DPPs) and evaluate their anti-asthmatic properties using a murine asthma model. Cur-PLGA-DPPs were prepared using a top-down fabrication method. The prepared Cur-PLGA-DPPs had a mean particle size of 2.5 ± 0.4 μm and a zeta potential value of −34.6 ± 4.8 mV. Ex vivo biodistribution results showed that the Cur-PLGA-DPPs mainly accumulated in the lungs and liver after intravenous injection. Treatment with Cur-PLGA-DPPs effectively suppressed the infiltration of inflammatory cells in bronchoalveolar lavage fluid, and reduced bronchial wall thickening and goblet-cell hyperplasia compared to those in the phosphate-buffered-saline-treated control group. No significant changes in hematology and blood biochemistry parameters were observed after treatment with Cur-PLGA-DPPs. At equal curcumin concentrations, treatment with Cur-PLGA-DPPs exhibited better therapeutic efficacy than treatment with free curcumin. Our results suggest that the microscale Cur-PLGA-DPPs can be potentially used as a lung-targeted asthma therapy.

Adverse gastrointestinal effects of COX-2 Inhibitors for inflammatory diseases

2013 ◽  
Author(s):  
Alaa Rostom ◽  
Catherine Dube ◽  
Emilie Jolicoeur ◽  
Janet L. Joyce ◽  
Katherine Muir
Keyword(s):  
Inflammatory Diseases ◽  
Cox 2 ◽  
Cox 2 Inhibitors

scholarly journals Obstructive Sleep Apnea and Inflammation: Proof of Concept Based on Two Illustrative Cytokines

2019 ◽  
Vol 20 (3) ◽  
pp. 459 ◽  
Author(s):  
Leila Kheirandish-Gozal ◽  
David Gozal
Keyword(s):  
Obstructive Sleep Apnea ◽  
Sleep Apnea ◽  
Inflammatory Diseases ◽  
Sleep Apnea Syndrome ◽  
Special Focus ◽  
Normal Body Mass Index ◽  
Low Grade ◽  
Obstructive Sleep ◽  
Inflammatory Processes ◽  
Factor Α

Obstructive sleep apnea syndrome (OSAS) is a markedly prevalent condition across the lifespan, particularly in overweight and obese individuals, which has been associated with an independent risk for neurocognitive, behavioral, and mood problems as well as cardiovascular and metabolic morbidities, ultimately fostering increases in overall mortality rates. In adult patients, excessive daytime sleepiness (EDS) is the most frequent symptom leading to clinical referral for evaluation and treatment, but classic EDS features are less likely to be reported in children, particularly among those with normal body-mass index. The cumulative evidence collected over the last two decades supports a conceptual framework, whereby sleep-disordered breathing in general and more particularly OSAS should be viewed as low-grade chronic inflammatory diseases. Accordingly, it is assumed that a proportion of the morbid phenotypic signature in OSAS is causally explained by underlying inflammatory processes inducing end-organ dysfunction. Here, the published links between OSAS and systemic inflammation will be critically reviewed, with special focus on the pro-inflammatory cytokines tumor necrosis factor α (TNF-α) and interleukin 6 (IL-6), since these constitute classical prototypes of the large spectrum of inflammatory molecules that have been explored in OSAS patients.

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