Receptors

20 pages, 2387 KB

Open AccessArticle

The NR4A Orphan Receptor Modulator C-DIM12 Selectively Alters Inflammatory Mediators in Myeloid Cells

by Sarah Aldhafiri, Mariam Marai, Mohamed Ismaiel, Brenda Murphy, Hugh E. Giffney, Thomas J. Hall, Evelyn P. Murphy, Eoin P. Cummins and Daniel Crean

Receptors 2023, 2(4), 264-283; https://doi.org/10.3390/receptors2040018 - 18 Dec 2023

Viewed by 2041

Abstract

Orphan nuclear receptor subfamily 4A (NR4A) are key regulators of inflammatory responses, largely by their interactions with NF-κB. Over the last decade, several NR4A modulators have been developed, and they are showing potential as therapeutics, although their widespread use in laboratory settings is limited. Here, we have examined, using myeloid cell line THP-1, whether the NR4A modulator 3-[(4-Chlorophenyl)-(1H-indol-3-yl)methyl]-1H-indole (C-DIM12) can alter the inflammatory outcome of six inflammatory ligands: lipopolysaccharide (LPS), tumour necrosis factor alpha (TNFα), interleukin-1 beta (IL-1β), flagellin (FL), lipoteichoic acid (LTA), and zymosan (ZY). We demonstrate that C-DIM12 (10 µM) selectively alters the secretion of inflammatory chemokine MCP-1 following exposure to distinct inflammatory ligands in a concentration-dependent manner. Furthermore, data obtained from THP-1 Lucia cell experiments show that 10 µM C-DIM12, and not 1 µM C-DIM12, can significantly attenuate the increased NF-κB transcriptional activity observed following the exposure to several inflammatory ligands (LPS, FL, TNFα, LTA, and ZY). Lastly, experimental analysis confirms that the cellular action(s) of C-DIM12 is independent of changes in metabolic parameters. Thus, these data contribute to the understanding of how the NR4A modulator C-DIM12 alters inflammatory responses in a myeloid cell following exposure to multiple ligands. Full article

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13 pages, 991 KB

Open AccessReview

Association of Bitter Taste Receptors with Obesity and Diabetes and Their Role in Related Tissues

by Eisuke Kato and Shota Oshima

Receptors 2023, 2(4), 251-263; https://doi.org/10.3390/receptors2040017 - 5 Dec 2023

Cited by 7 | Viewed by 5881

Abstract

Taste 2 receptors (T2Rs) are G-protein-coupled receptors responsible for sensing bitter tastes. Many studies have shown the expression of T2Rs in extraoral tissues and the unique role of T2Rs in each tissue. Single-nucleotide polymorphisms of T2Rs are associated with the risk of obesity and diabetes, and the organs/tissues associated with the development of these metabolic diseases, including the intestine, adipose, muscle, liver, and pancreas, are reported to express T2R genes. This result suggests that T2Rs in extraoral tissues contribute to the development of obesity and diabetes. In this narrative review, we summarize current knowledge of the associations of T2Rs with obesity and diabetes, provide an overview of extraoral tissues that are associated with the development of obesity and diabetes that express T2R genes, and summarize the current knowledge of T2Rs. Full article

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19 pages, 906 KB

Open AccessFeature PaperReview

Evidence for the Involvement of the Tachykinin NK1 Receptor in Acute Inflammation of the Central Nervous System

by Renée J. Turner and Alan J. Nimmo

Receptors 2023, 2(4), 232-250; https://doi.org/10.3390/receptors2040016 - 15 Nov 2023

Cited by 3 | Viewed by 2847

Abstract

Neuroinflammation is considered to be a significant component in a range of neuropathologies. Unfortunately, whilst its role is well recognised, the options for therapeutic intervention are limited. As such, there is a need to identify novel targets in order to increase treatment options. Given its role as both a neurotransmitter and an immune modulator, substance P (SP) and its NK1 receptor (NK1R) have been widely studied as a potential therapeutic target. There is evidence that NK1R antagonists may exert beneficial effects in a range of conditions, including traumatic brain injury and stroke. Blocking the NK1R has been shown to reduce blood–brain barrier dysfunction, reduce cerebral oedema, and reduce the levels of pro-inflammatory cytokines. These actions are associated with improved survival and functional outcomes. The NK1R has also been shown to be involved in the inflammatory reaction to CNS infection, and hence antagonists may have some benefit in reducing infection-driven inflammation. However, the NK1R may also play a role in the host immune response to infection, and so here, the potential beneficial and detrimental effects need to be carefully balanced. The purpose of this review is to provide a summary of evidence for the involvement of the NK1R in acute CNS inflammation, particularly in the context of traumatic brain injury and stroke. Full article

(This article belongs to the Special Issue Biological and Pharmacological Aspects of the Neurokinin-1 Receptor)

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12 pages, 2080 KB

Open AccessReview

The Role of Substance P and NK1 Receptors in Mild to Severe Traumatic Brain Injury: From CTE to ICP

by Robert Vink and Frances Corrigan

Receptors 2023, 2(4), 220-231; https://doi.org/10.3390/receptors2040015 - 11 Nov 2023

Viewed by 3088

Abstract

Binding of substance P to the tachykinin NK1 receptor is involved in numerous physiological and pathophysiological processes ranging from modulation of sensory and motor function to inflammation, cancer, and brain injury, amongst others. NK1 antagonists therefore have enormous potential as a therapeutic intervention in a wide variety of human disease states, albeit that the clinical potential is yet to be fully realised. In the current review, the role of substance P in the pathophysiology of traumatic brain injury (TBI) will be discussed, summarising both experimental and clinical observations in mild, moderate, and severe TBI. In addition, the potential for NK1 antagonists to be a valuable therapeutic intervention against chronic traumatic encephalopathy (CTE) after repeated concussive brain injury as well as raised intracranial pressure (ICP) following severe TBI will be addressed, highlighting the various pathophysiological processes that are attenuated by the intervention. Full article

(This article belongs to the Special Issue Biological and Pharmacological Aspects of the Neurokinin-1 Receptor)

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16 pages, 1953 KB

Open AccessReview

Regulation of Cholesterol Transporters by Nuclear Receptors

by Michinori Matsuo

Receptors 2023, 2(4), 204-219; https://doi.org/10.3390/receptors2040014 - 9 Oct 2023

Cited by 5 | Viewed by 3206

Abstract

Atherosclerosis is a pathological condition characterized by the accumulation of plaques in the arteries, leading to cardiovascular diseases. The deposition of cholesterol in peripheral cells increases the risk of atherosclerosis. Reverse cholesterol transport (RCT) is essential to reduce the risk of atherosclerosis because it removes excessive cholesterol from the peripheral tissues. ATP-binding cassette transporters such as ABCA1, ABCG1, ABCG5, and ABCG8 are involved in the efflux of cholesterol. The upregulation of these ABC transporters enhances RCT, thereby promoting the removal of excess cholesterol from the body. The expression and activity of ABC transporters are regulated by transcriptional and post-transcriptional mechanisms, as well as by post-translational modifications. In this review, the regulation of ABC transporters by nuclear receptors such as farnesoid X receptor, liver X receptor, retinoid X receptor, retinoic acid receptor, and peroxisome proliferator-activated receptors is discussed. Pharmacological and natural compounds serving as agonists for the nuclear receptors have been identified to elevate the mRNA levels of the transporters. Consequently, it is anticipated that these compounds will attenuate the development of atherosclerosis through stimulation of the ABC transporters, thereby enhancing RCT and fecal cholesterol excretion. Understanding these regulatory processes can aid in the development of therapeutic approaches to prevent atherosclerosis. Full article

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Receptors, Volume 2, Issue 4 (December 2023) – 5 articles

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