ArticleFASEB journal : official publication of the Federation of American Societies for Experimental Biology2013
Systematic analysis of rat 12/15-lipoxygenase enzymes reveals critical role for spinal eLOX3 hepoxilin synthase activity in inflammatory hyperalgesia.
Article in FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 32 papers.
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Who cites it
32 citing papers in PubMed, 47 citations in OpenAlex.
- Tumour-associated high endothelial venules drive portal-specific immune evasion in lymph nodes via ALOX12.Nature communications · 2026Article
- The role of ALOX15 in inflammation-related diseases.Frontiers in immunology · 2026Review
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- Natural flavonoids from herbs and nutraceuticals as ferroptosis inhibitors in central nervous system diseases: current preclinical evidence and future perspectives.Frontiers in pharmacology · 2025Review
- Elevated ALOX12 in renal tissue predicts progression in diabetic kidney disease.Renal failure · 2024Article
- Identifying genetic targets in clinical subtypes of Parkinson's disease for optimizing pharmacological treatment strategies.Signal transduction and targeted therapy · 2024Article
- The Predictive Value of Plasma Bioactive Lipids on Craving in Human Volunteers With Alcohol Use Disorder.Biological psychiatry global open science · 2024Article
- Harnessing ferroptosis for enhanced sarcoma treatment: mechanisms, progress and prospects.Experimental hematology & oncology · 2024Review
- Targeting ferroptosis opens new avenues for the development of novel therapeutics.Signal transduction and targeted therapy · 2023Review
- Association between single nucleotide variants and severe chronic pain in older adult patients after lower extremity arthroplasty.Journal of orthopaedic surgery and research · 2023Article
- Review
- A review on the relationship between Arachidonic acid 15-Lipoxygenase (ALOX15) and diabetes mellitus.PeerJ · 2023Review
- Chronic social defeat stress increases the amounts of 12-lipoxygenase lipid metabolites in the nucleus accumbens of stress-resilient mice.Scientific reports · 2022Article
- Role of leukotriene B4 (LTB4)-LTB4 receptor 1 signaling in post-incisional nociceptive sensitization and local inflammation in mice.PloS one · 2022Article
- Nordihydroguaiaretic Acid as a Novel Substrate and Inhibitor of CatecholMolecules (Basel, Switzerland) · 2021Article
- Ferroptosis: mechanisms and links with diseases.Signal transduction and targeted therapy · 2021Review
- The enzymology of human eicosanoid pathways: the lipoxygenase branches.Molecular biology reports · 2020Review
- Cholecalciferol (Vitamin DMolecular neurobiology · 2019Article
- Oxidized Lipids in Persistent Pain States.Frontiers in pharmacology · 2019Review
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11 authors at 1 institution in 1 country.
Funding
Abstract
Previously, we observed significant increases in spinal 12-lipoxygenase (LOX) metabolites, in particular, hepoxilins, which contribute to peripheral inflammation-induced tactile allodynia. However, the enzymatic sources of hepoxilin synthase (HXS) activity in rats remain elusive. Therefore, we overexpressed each of the 6 rat 12/15-LOX enzymes in HEK-293T cells and measured by LC-MS/MS the formation of HXB3, 12-HETE, 8-HETE, and 15-HETE from arachidonic acid (AA) at baseline and in the presence of LOX inhibitors (NDGA, AA-861, CDC, baicalein, and PD146176) vs. vehicle-treated and mock-transfected controls. We detected the following primary intrinsic activities: 12-LOX (Alox12, Alox15), 15-LOX (Alox15b), and HXS (Alox12, Alox15). Similar to human and mouse orthologs, proteins encoded by rat Alox12b and Alox12e possessed minimal 12-LOX activity with AA as substrate, while eLOX3 (encoded by Aloxe3) exhibited HXS without 12-LOX activity when coexpressed with Alox12b or supplemented with 12-HpETE. CDC potently inhibited HXS and 12-LOX activity in vitro (relative IC50s: CDC, ~0.5 and 0.8 μM, respectively) and carrageenan-evoked tactile allodynia in vivo. Notably, peripheral inflammation significantly increased spinal eLOX3; intrathecal pretreatment with either siRNA targeting Aloxe3 or an eLOX3-selective antibody attenuated the associated allodynia. These findings implicate spinal eLOX3-mediated hepoxilin synthesis in inflammatory hyperesthesia and underscore the importance of developing more selective 12-LOX/HXS inhibitors.
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