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Beneficial Effects of Omega-3 Fatty Acids on Cardiovascular Disease
Published in Catherina Caballero-George, Natural Products and Cardiovascular Health, 2018
Estela Guerrero De León, Mahabir Prashad Gupta, Juan Antonio Morán-Pinzón
Meanwhile, the actions of RvD1 are mediated by two G protein-coupled receptors (GPCR), ALX/FPR2 and GPR32, which also regulate specific microRNAs (miRNAs) and their target genes in new resolution circuits. Interaction with ALX/FPR2 signals could control infiltration of polymorphonuclear neutrophils (PMN) and stimulate macrophagocytosis of apoptotic PMNs (Chiang et al., 2006), while it is suggested that the GPR32 also plays a key role in mediating the effects of RvD1 on human macrophages (Schmid et al., 2016). Despite numerous findings that document the molecular actions associated with the anti-inflammatory effects of ω-3 PUFAs, crucial aspects of signaling mechanisms and downstream interactions remain to be elucidated.
Angiogenesis and Roles of Adhesion Molecules in Psoriatic Disease
Published in Siba P. Raychaudhuri, Smriti K. Raychaudhuri, Debasis Bagchi, Psoriasis and Psoriatic Arthritis, 2017
Asmita Hazra, Saptarshi Mandal
Human cathelicidin antimicrobial protein hCAP18 is the only human cathelicidin whose mature fragment is LL37, which is a multifunctional polypeptide. LL37 is a basic and hydrophobic amino acid–rich 37-amino-acid peptide that is positively charged (6+) at pH 7.4. It is a naturally disordered peptide that folds upon binding to negatively charged nonself or hidden-self surfaces (e.g., DNA or f-actin). It aids in the development of the danger signal, and thus is a central component of innate immunity. Originally discovered for its microbicidal activity, LL37 transactivates the endothelial growth factor receptor (EGFR), inducing cytokine release and cell migration. It stimulates chemotaxis and angiogenesis through the GPCR, FPR2. LL37 is an inducer of tissue repair and wound healing, as well as tumor growth and progression. It is upregulated in ovarian, breast, and lung tumors. LL37 also recruits multipotent mesenchymal stromal cells into tumors.
Cardiovascular Disease and Oxidative Stress
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
Marco Fernandes, Alisha Patel, Holger Husi
LOXs are expressed in many cellular microenvironments, including epithelium, immune and tumour, which are involved in a diversity of physiological functions and pathological states, such as inflammation, asthma, skin disorders (e.g. ichthyosis), and as well oncogenesis (Mashima and Okuyama, 2015). When 5-LOX oxidizes AA, in addition to the consecutive reduction steps to yield hydroperoxides (-ROOH) and hydroxides (OH−), they produce key inflammatory mediators, leukotrienes, which transduce pro-inflammatory signals to elicit leukocytes adhesion, chemotaxis and aggregation (Radmark et al., 2007). In animal models of atherosclerosis was observed that targeting leukotriene receptors lessens disease progression (Poeckel and Funk, 2010), in humans this was confirmed by following sections of the population treated with leukotriene receptor antagonists (LTRAs), such as in asthma conditions, and they infer an association with diminished cardiovascular risk (Back et al., 2013; Ingelsson et al., 2012). On the other hand, consecutive lipoxygenation of AA produces lipoxins, A4 (LXA4) and B4 (LXB4), which are anti-inflammatory and transduce resolution of inflammation and restores tissue homeostasis (Chandrasekharan and Sharma-Walia, 2015; Karra et al., 2015). Supplementation with omega-3 was seen to induce inflammation resolution and decrease atherosclerosis (Back, 2017). In atherosclerotic mice, the G protein-coupled lipoxin A4 receptor (ALX)/formyl peptide receptor (FPR2) is activated by lipoxins and peptide agonists, in which FPR2/ALX disruption lessens the size of the atherosclerotic lesion, but promotes plaque instability (Petri et al., 2015). In cardiac tissue of streptozotocin (STZ)-induced diabetic mice, 12/15-LOX isoforms triggered inflammation and oxidative stress, in opposition, Alox15-deficient mice yielded decreased expression of TNF-alpha and nuclear factor (NF)-κB and eradicated STZ-induced reactive oxygen species production (Suzuki et al., 2015). Targeting 12/15-LOX isoforms could lead to a potential treatment of diabetic cardiomyopathy (DCM), a well-known risk factor of the atherogenesis process and heart failure (Kayama et al., 2009; Suzuki et al., 2015).
Age-associated Ligand-receptor Interactions Imputed from Nasopharyngeal Transcriptomes of COVID-19 Patients
Published in Immunological Investigations, 2022
A recent study of immune cell composition in bronchoalveolar lavage fluid has shown increased expression of pro-inflammatory immune cells expressing more CCR1 and CXCR2 receptors in severe COVID-19 cases (Liao et al. 2020). Indeed, the present study has also shown increased interactions with these receptors in older patients between the NP-M interactions (Figure 1A). Interactions with these receptors were also increased within the microenvironment (M-M) in older patients (Figure 2A). CXCR2 signaling is also a chemokine axis that regulates neutrophil release form the bone marrow (Eash et al. 2010). This is further supported by the increased relative proportions of neutrophils in older patients suggested from computational gene expression deconvolution (Figure 3). Furthermore, CXCL1 and CXCL6 ligands were also shown to be involved in these interactions. CXCL1 secretion has been associated with pro-inflammatory immune cell infiltration (Susek et al. 2018). Formyl peptide receptor 2 (FPR2) interaction with amyloid precursor protein (APP) was also higher in older patients and is implicated in regulating the activation of inflammatory cells (Park et al. 2019). Some notable M-M interactions included SELL receptor interactions with complement factor H (CFH), PODXL2, and CD34, which were decreased relative to the younger patient cohort (Figure 2A). CFH participates in regulation of complement activation (Rodríguez de Córdoba et al. 2004).
Cathelicidin-mediated lipopolysaccharide signaling via intracellular TLR4 in colonic epithelial cells evokes CXCL8 production
Published in Gut Microbes, 2020
Ravi Holani, Anshu Babbar, Graham A. D. Blyth, Fernando Lopes, Humberto Jijon, Derek M. McKay, Morley D. Hollenberg, Eduardo R. Cobo
Apart from their direct bacteriocidal activities, cathelicidins were shown to modulate inflammatory responses, primarily in hematopoietic cells.2 Cathelicidins enhance chemokine expression (CXCL1, CXCL8, CCL2, CCL5 and CCL10) by monocytes and reduce TNF-α production by macrophages challenged with lipopolysaccharide (LPS), lipotechoic acid (LTA) or lipoarabinomannan.5,15,17 It has been proposed that cathelicidins recruit monocytes, neutrophils and eosinophils,18,20 possibly by activating chemotactic formyl peptide receptor 2 (FPR2).19,21 Although cathelicidins are produced by intestinal epithelial cells, potentially to ward off bacteria, a direct effect of cathelicidins on the gut epithelium and in the context of enteric infectious bacterial disease is unknown.
What is the current value of fluorescence polarization assays in small molecule screening?
Published in Expert Opinion on Drug Discovery, 2020
FP-based assays will continue to be in the forefront of biochemical HTS technologies. Biological interactions are better described when the interacting partners are considered to be in their ‘natural’ milieu. Thus, FP has the advantage of resisting some significant in situ optical interferences [2,p.813,4]. Although the development of suitable fluorescent tracers may be complicated in special cases, their use pays off quickly because of the simplicity and reliability of FP-based binding assays. Furthermore, malfunctioning of the G-protein-coupled galanin receptor type 2, melanocortin 1 receptor, and formyl peptide receptor 2 is correlated with epilepsy, obesity, and Alzheimer’s disease, respectively. Many enzymes and G-protein-coupled receptors (GPCRs) are associated with severe diseases and therefore necessitate new and improved drugs. Thus, improved screening assays are an important component of the discovery of novel compounds. Alternatively, SPR has been used to screen 6,369 compounds as potential GPCR ligands (neurotensin receptor 1) [8].