Rheumatoid arthritis (RA) is an autoimmune-mediated disease with the highest disability rate. Sporidiobolus pararoseus polysaccharides (SPP) have been demonstrated to have anti-rheumatoid and microbiota-modulatory effects; however, the underlying mechanisms remain unclear. This study employed collagen-induced arthritis (CIA) mice to explore the metabolic and genetic pathways. The results revealed SPP intervention significantly reduced the serum levels of rheumatoid and pro-inflammatory complement factors. SPP promoted the transition of macrophages of CIA mice toward the M2 phenotype (F4/80⁺/CD206⁺) from an inflammatory phenotype (F4/80⁺/CD86⁺) using flow cytometry analysis. A total of 44 metabolites were upregulated, and 110 metabolites were significantly downregulated by SPP compared to those in RA group. The decreased metabolites, 12(S)-HPETE, prostaglandin H2, 15-HETE, hepoxilin B3, and 15-keto-prostaglandin F2a, were mostly enriched in arachidonic acid metabolism (enrichment = 11.4 %), which was highly correlated with the anti-rheumatic activity of SPP. Gene expression analysis revealed that SPP significantly regulated OPG/RANKL/TRAF6 signaling pathway, stimulating osteogenic remodeling. Furthermore, arachidonic acid metabolism was identified as the critical metabolic driver of RA phenotypes and osteoclast differentiation, potentially associated with SPP-reshaped intestinal microbiota (i.e., Rikenellaceae_RC9_gut_group, Bacteroides, and Parabacteroides). Collectively, this study utilized an integrated approach of metabolomics and gene expression analysis to investigate the regulatory role of SPP in RA progression.

01 Oct 2024·Prostaglandins & Other Lipid Mediators

Mucosal LTE4, PGD2 and 15(S)-HETE as potential prognostic markers for polyp recurrence in chronic rhinosinusitis

Article

Author: Tang, Xiao ; Kumlin, Maria ; Ryott, Michael ; Svedberg, Marie ; Jangard, Mattias ; Nordström, Axel

BACKGROUNDAltered biosynthesis of eicosanoids is linked to type 2 inflammation in chronic rhinosinusitis with nasal polyps (CRSwNP), but their role in recalcitrant NPs is unclear.OBJECTIVESWe sought to identify endotypes that are linked to recalcitrant CRSwNP, based on eicosanoids, their biosynthetic enzymes, and receptors as well as cytokines and the presence of eosinophils and mast cells in recurrent NPs.METHODSMucosal tissue collected at the time of sinus surgery from 54 patients with CRSwNP and 12 non-CRS controls were analysed for leukotriene (LT) E4, prostaglandin (PG) D2, 15(S)-hydroxyeicosatetraenoic acid (15(S)-HETE) and 17 cytokines with ELISAs and Bio-Plex immunoassays. Patient subgroups were identified by cluster analysis and the probability of NP recurrence were tested with logistic regression analyses. Gene expressions were analysed with qPCR. Tryptase and eosinophil-derived neurotoxin (EDN) were measured with ELISAs as indications of the presence of mast cells and eosinophils, respectively.RESULTSClustering of patients showed that an inflammatory signature characterised by elevated LTE₄, PGD₂, 15(S)-HETE and IL-13 was associated with NP recurrence. Previous NP surgery as well as aspirin-exacerbated respiratory disease were significantly more common among these patients. Expression of cyclooxygenase 1 was the only gene associated with NP recurrence. Levels of EDN, but not tryptase, were significantly higher in patients with recurrent NPs.CONCLUSIONDistinguishing endotypes that include LTE₄, PGD₂, 15HETE and conventional biomarkers of type 2 inflammation could help predict recurrent nasal polyposis and thus identify cases of recalcitrant CRSwNP.

16 Sep 2024·Doklady. Biochemistry and biophysics

The Role of Hydroxyeicosatetraenoic Acids in the Regulation of Inflammation in Bronchial Asthma.

Article

Author: Kytikova, O Yu ; Kovalenko, I S ; Denisenko, Yu K ; Novgorodtseva, T P

Hydroperoxyeicosatetraenoic acids (HETEs) are metabolites of arachidonic acid that are oxidized by a family of enzymes including cyclooxygenase, lipoxygenase, and cytochrome P450 enzymes. These enzymes are widely present in various organs and tissues, and the HETEs they synthesize perform an important function in the regulation of immune reactions and haemostasis processes under physiological and pathophysiological conditions. More researchers confirm the role of these oxidized metabolites in modulating inflammation in asthma. The high production of HETEs in allergic and severe asthma indicates their involvement in the processes of an acute inflammatory response. On the other hand, disturbance of the metabolic transformation of arachidonic acid contributes to the development of chronic inflammation due to insufficient synthesis of mediators that resolve inflammatory processes. Several HETEs have both pro-inflammatory and anti-inflammatory effects, which underscores the ongoing interest in their involvement in the pathogenesis of asthma. At the same time, research results are scarce. Based on an analysis of the literature, the pathways of metabolic transformation of 5-HETE, 12-HETE, and 15-HETE with the participation of cyclooxygenases, lipoxygenases, and cytochrome P-450, as well as their role in asthma pathogenesis, were discussed. The PubMed database was searched for information covering the last five years using selected inclusion criteria. Information queries included the following set of keywords: "bronchial asthma, hydroxyeicosatetraenoic acids, 5-HETE, 12-HETE, 15-HETE." Literature data indicate that the role of HETEs in human physiology and pathology, including the modulation of inflammation in asthma, requires comprehensive study to selectively modulate the enzymatic pathways of arachidonic acid metabolism leading to the production of these mediators.

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Indication	Highest Phase	Country/Location	Organization	Date
Dry Eye Syndromes	Phase 1	US	-	-
Diabetic Retinopathy	Preclinical	EG	Augusta University	01 May 2016
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