A5070292545- Eicosanoids and Hypertension Pharmacology
- Fatty Acid Research and Health
- Inflammatory mediators and NSAID effects
- Bioactive Compounds and Antitumor Agents
- Receptor Mechanisms and Signaling
- Retinal Development and Disorders
- Genomics, phytochemicals, and oxidative stress
- Bioactive natural compounds
- Fungal Biology and Applications
- Plant-derived Lignans Synthesis and Bioactivity
- Ferroptosis and cancer prognosis
- Axon Guidance and Neuronal Signaling
- Sphingolipid Metabolism and Signaling
- Natural product bioactivities and synthesis
- Biochemical Analysis and Sensing Techniques
- Neuroscience and Neuropharmacology Research
- Influenza Virus Research Studies
- Microbial metabolism and enzyme function
- Antiplatelet Therapy and Cardiovascular Diseases
- Phytoestrogen effects and research
- Synthesis and biological activity
- Plant-Microbe Interactions and Immunity
- Herbal Medicine Research Studies
- Biological and pharmacological studies of plants
- Neuroinflammation and Neurodegeneration Mechanisms
University of California, Santa Cruz
2011-2023
University of California, Berkeley
2015
Oregon State University
2013
Objectives N‐acetylcysteine (NAC) is a clinically approved thiol‐containing redox modulatory compound currently in trials for many neurological and psychiatric disorders. Although generically labeled as an “antioxidant,” poor understanding of its site(s) action barrier to use practice. Here, we examined the efficacy mechanism NAC rodent models hemorrhagic stroke. Methods Hemin was used model ferroptosis stroke cultured neurons. Striatal infusion collagenase intracerebral hemorrhage (ICH)...
A key challenge facing drug discovery today is variability of the target between species, such as with 12/15-lipoxygenase (12/15-LOX), which contributes to ischemic brain injury, but its human and rodent isozymes have different inhibitor specificities. In current work, we utilized a quantitative high-throughput (qHTS) screen identify compound 1 (ML351), novel chemotype for 12/15-LOX inhibition that has nanomolar potency (IC50 = 200 nM) against protective oxidative glutamate toxicity in mouse...
Human lipoxygenases (LOXs) are a family of iron-containing enzymes which catalyze the oxidation polyunsaturated fatty acids to provide corresponding bioactive hydroxyeicosatetraenoic acid (HETE) metabolites. These eicosanoid signaling molecules involved in number physiologic responses such as platelet aggregation, inflammation, and cell proliferation. Our group has taken particular interest platelet-type 12-(S)-LOX (12-LOX) because its demonstrated role skin diseases, diabetes, hemostasis,...
We report the discovery of novel small molecule inhibitors platelet-type 12-human lipoxygenase, which display nanomolar activity against purified enzyme, using a quantitative high-throughput screen (qHTS) on library 153607 compounds. These compounds also exhibit excellent specificity, >50-fold selectivity vs paralogues, 5-human reticulocyte 15-human lipoxygenase type-1, and epithelial type-2, >100-fold ovine cyclooxygenase-1 human cyclooxygenase-2. Kinetic experiments indicate this chemotype...
In the inner plexiform layer (IPL) of mouse retina, ~70 neuronal subtypes organize their neurites into an intricate laminar structure that underlies visual processing. To find recognition proteins involved in lamination, we utilized microarray data from 13 to identify differentially-expressed extracellular and performed a high-throughput biochemical screen. We identified ~50 previously-unknown receptor-ligand pairs, including new interactions among members FLRT Unc5 families. These show...
The two oxylipins 7S,14S-dihydroxydocosahexaenoic acid (diHDHA) and 7S,17S-diHDHA [resolvin D5 (RvD5)] have been found in macrophages infectious inflammatory exudates are believed to function as specialized pro-resolving mediators (SPMs). Their biosynthesis is thought proceed through sequential oxidations of DHA by lipoxygenase (LOX) enzymes, specifically, human 5-LOX (h5-LOX) first 7(S)-hydroxy-4Z,8E,10Z,13Z,16Z,19Z-DHA (7S-HDHA), followed platelet 12-LOX (h12-LOX) form...
The biosynthetic gene cluster for the pyralomicin antibiotics has been cloned and sequenced from Nonomuraea spiralis IMC A-0156. 41 kb contains 27 ORFs predicted to encode all of functions biosynthesis. This includes nonribosomal peptide synthetases (NRPS) polyketide synthases (PKS) required formation benzopyranopyrrole core unit, as well a suite tailoring enzymes (e.g., four halogenases, an O-methyltransferase, N-glycosyltransferase) necessary further modifications structure....
Lipoxygenases, important enzymes in inflammation, can regulate their substrate specificity by allosteric interactions with own hydroperoxide products. In this work, addition of both 13-(S)-hydroxy-(9Z,11E)-octadecadienoic acid [13-(S)-HODE] and 13-(S)-hydroperoxy-(6Z,9Z,11E)-octadecatrienoic to human epithelial 15-lipoxygenase-2 (15-LOX-2) increases the kcat/KM ratio arachidonic (AA) γ-linolenic (GLA) 4-fold. 13-(S)-HODE achieves change activating kcat/KM(AA) but inhibiting kcat/KM(GLA),...
Human reticulocyte 15-lipoxygenase-1 (h15-LOX-1 or ALOX15) and platelet 12-lipoxygenase (h12-LOX ALOX12) catalysis of docosahexaenoic acid (DHA) the maresin precursor, 14S-hydroperoxy-4Z,7Z,10Z,12E,16Z,19Z-docosahexaenoic (14S-HpDHA), were investigated to determine their product profiles relative rates in biosynthesis key intermediate, 13S,14S-epoxy-4Z,7Z,9E,11E,16Z,19Z-docosahexaenoic (13S,14S-epoxy-DHA). Both enzymes converted DHA 14S-HpDHA, with h12-LOX having a 39-fold greater kcat/KM...
The antiplatelet effect of polyunsaturated fatty acids is primarily attributed to its metabolism bioactive metabolites by oxygenases, such as lipoxygenases (LOX). Platelets have demonstrated the ability generate 15-LOX-derived (15-oxylipins); however, whether 15-LOX in platelet or required for formation 15-oxylipins remains unclear. This study seeks elucidate and determine their mechanistic effects on reactivity. In this study, 15-HETrE, 15-HETE, 15-HEPE attenuated collagen-induced...
We report the discovery of a novel dual inhibitor targeting fungal sterol 14α-demethylase (CYP51 or Erg11) and human 5-lipoxygenase (5-LOX) with improved potency against 5-LOX due to its reduction iron center by phenylenediamine core. A series potent inhibitors containing core, were synthesized that exhibit nanomolar >30-fold selectivity LOX paralogs, platelet-type 12-human lipoxygenase, reticulocyte 15-human lipoxygenase type-1, epithelial type-2, >100-fold ovine cyclooxygenase-1...
The oxylipins, 5S,12S-dihydroxy-6E,8Z,10E,14Z-eicosatetraenoic acid (5S,12S-diHETE) and 5S,15S-dihydroxy-6E,8Z,11Z,13E-eicosatetraenoic (5S,15S-diHETE), have been identified in cell exudates chemotactic activity toward eosinophils neutrophils. Their biosynthesis has proposed to occur by sequential oxidations of arachidonic (AA) lipoxygenase enzymes, specifically through oxidation AA h5-LOX followed h12-LOX, h15-LOX-1, or h15-LOX-2. In this work, h15-LOX-1 demonstrates altered positional...
In this study, we have investigated 16 isoflavone and isoflavan derivatives as potential inhibitors of human lipoxygenase (platelet 12‐lipoxygenase, reticulocyte 15‐lipoxygenase‐1, epithelial 15‐lipoxygenase‐2). The flavonoid baicalein, a known inhibitor, was used positive control. Four compounds, 6,7‐dihydroxy‐3′‐chloroisoflavone ( 1c ), 7‐hydroxy‐8‐methyl‐4′‐chloroisoflavan 5a 7,8‐dihydroxy‐4′‐methylisoflavan 5b 7,8‐dihydroxy‐3′‐methylisoflavan 5c were effective 12‐lipoxygenases...
Continuing our search to find more potent and selective 5-LOX inhibitors, we present now the enzymatic evaluation of seventeen isoflavones (IR) nine isoflavans (HIR), their in vitro cellulo potency against human leukocyte 5-LOX. Of 26 compounds tested, 10 9 possessed micromolar potency, but only three were (IR-2, HIR-303, HIR-309), with IC50 values at least times lower than those 12-LOX, 15-LOX-1, 15-LOX-2. these three, IR-2 (6,7-dihydroxy-4-methoxy-isoflavone, known as texasin) was most...
ABSTRACT The oxylipins, 7S,14S-diHDHA and 7S,17S-diHDHA (RvD5), have been found in macrophages exudates are believed to function as specialized pro-resolving mediators (SPM’s). Their biosynthesis is thought proceed through sequential oxidations of docosahexaenoic acid (DHA) by lipoxygenase enzymes, specifically h5-LOX first 7S-HDHA, followed h12-LOX form or h15-LOX-1 (RvD5). In this work, we determined that oxidation 7S-HpDHA can be performed either h15-LOX-1, with similar kinetics. at C14...