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Pharmacology & Therapeutics Aug 2023Docosahexaenoic acid (DHA, 22:6n-3) accretion in brain phospholipids is critical for maintaining the structural fluidity that permits proper assembly of protein... (Review)
Review
Docosahexaenoic acid (DHA, 22:6n-3) accretion in brain phospholipids is critical for maintaining the structural fluidity that permits proper assembly of protein complexes for signaling. Furthermore, membrane DHA can be released by phospholipase A and act as a substrate for the synthesis of bioactive metabolites that regulate synaptogenesis, neurogenesis, inflammation, and oxidative stress. Thus, brain DHA is consumed through multiple pathways including mitochondrial β-oxidation, autoxidation to neuroprostanes, as well as enzymatic synthesis of bioactive metabolites including oxylipins, synaptamide, fatty-acid amides, and epoxides. By using models developed by Rapoport and colleagues, brain DHA loss has been estimated to be 0.07-0.26 μmol DHA/g brain/d. Since β-oxidation of DHA in the brain is relatively low, a large portion of brain DHA loss may be attributed to the synthesis of autoxidative and bioactive metabolites. In recent years, we have developed a novel application of compound specific isotope analysis to trace DHA metabolism. By the use of natural abundance in C-DHA in the food supply, we are able to trace brain phospholipid DHA loss in free-living mice with estimates ranging from 0.11 to 0.38 μmol DHA/g brain/d, in reasonable agreement with previous methods. This novel fatty acid metabolic tracing methodology should improve our understanding of the factors that regulate brain DHA metabolism.
Topics: Mice; Animals; Docosahexaenoic Acids; Brain; Inflammation; Signal Transduction; Oxidative Stress
PubMed: 37201738
DOI: 10.1016/j.pharmthera.2023.108437 -
Nutrients May 2024Osteoarthritis (OA) is a degenerative joint disease characterized by the destruction of the articular cartilage, resulting in a pro-inflammatory response. The... (Review)
Review
Osteoarthritis (OA) is a degenerative joint disease characterized by the destruction of the articular cartilage, resulting in a pro-inflammatory response. The progression of OA is multifactorial and is influenced by the underlying cause of inflammation, which includes but is not limited to trauma, metabolism, biology, comorbidities, and biomechanics. Although articular cartilage is the main tissue affected in osteoarthritis, the chronic inflammatory environment negatively influences the surrounding synovium, ligaments, and subchondral bone, further limiting their functional abilities and enhancing symptoms of OA. Treatment for osteoarthritis remains inconsistent due to the inability to determine the underlying mechanism of disease onset, severity of symptoms, and complicating comorbidities. In recent years, diet and nutritional supplements have gained interest regarding slowing the disease process, prevention, and treatment of OA. This is due to their anti-inflammatory properties, which result in a positive influence on pain, joint mobility, and cartilage formation. More specifically, omega-3 polyunsaturated fatty acids (PUFA) have demonstrated an influential role in the progression of OA, resulting in the reduction of cartilage destruction, inhibition of pro-inflammatory cytokine cascades, and production of oxylipins that promote anti-inflammatory pathways. The present review is focused on the assessment of evidence explaining the inflammatory processes of osteoarthritis and the influence of omega-3 supplementation to modulate the progression of osteoarthritis.
Topics: Humans; Osteoarthritis; Fatty Acids, Omega-3; Dietary Supplements; Cartilage, Articular; Disease Progression; Inflammation; Anti-Inflammatory Agents; Animals
PubMed: 38892583
DOI: 10.3390/nu16111650 -
The New Phytologist Sep 2023Jasmonate (JA) re-programs metabolism to confer resistance to diverse environmental threats. Jasmonate stimulates the degradation of JASMONATE ZIM-DOMAIN (JAZ) proteins...
Jasmonate (JA) re-programs metabolism to confer resistance to diverse environmental threats. Jasmonate stimulates the degradation of JASMONATE ZIM-DOMAIN (JAZ) proteins that repress the activity of MYC transcription factors. In Arabidopsis thaliana, MYC and JAZ are encoded by 4 and 13 genes, respectively. The extent to which expansion of the MYC and JAZ families has contributed to functional diversification of JA responses is not well understood. Here, we investigated the role of MYC and JAZ paralogs in controlling the production of defense compounds derived from aromatic amino acids (AAAs). Analysis of loss-of-function and dominant myc mutations identified MYC3 and MYC4 as the major regulators of JA-induced tryptophan metabolism. We developed a JAZ family-based, forward genetics approach to screen randomized jaz polymutants for allelic combinations that enhance tryptophan biosynthetic capacity. We found that mutants defective in all members (JAZ1/2/5/6) of JAZ group I over-accumulate AAA-derived defense compounds, constitutively express marker genes for the JA-ethylene branch of immunity and are more resistant to necrotrophic pathogens but not insect herbivores. In defining JAZ and MYC paralogs that regulate the production of amino-acid-derived defense compounds, our results provide insight into the specificity of JA signaling in immunity.
Topics: Arabidopsis Proteins; Proto-Oncogene Proteins c-myc; Repressor Proteins; Tryptophan; Signal Transduction; Arabidopsis; Cyclopentanes; Oxylipins; Gene Expression Regulation, Plant
PubMed: 37403524
DOI: 10.1111/nph.19114 -
Plant Science : An International... Oct 2023JAZ proteins are involved in the regulation of the jasmonate signaling pathway, which is responsible for various physiological processes, such as defense response,... (Review)
Review
JAZ proteins are involved in the regulation of the jasmonate signaling pathway, which is responsible for various physiological processes, such as defense response, adaptation to abiotic stress, growth, and development in Arabidopsis. The conserved domains of JAZ proteins can serve as binding sites for a broad array of regulatory proteins and the diversity of these protein-protein pairings result in a variety of functional outcomes. Plant growth and defense are two physiological processes that can conflict with each other, resulting in undesirable plant trade-offs. Recent observations have revealed a distinguishing feature of JAZ4; it acts as negative regulator of both plant immunity and growth and development. We suggest that these complex biological processes can be decoupled at the JAZ4 regulatory node, due to prominent expression of JAZ4 in specific tissues and organs. This spatial separation of actions could explain the increased disease resistance and size of the plant root and shoot in the absence of JAZ4. At the tissue level, JAZ4 could play a role in crosstalk between hormones such as ethylene and auxin to control organ differentiation. Deciphering biding of JAZ4 to specific regulators in different tissues and the downstream responses is key to unraveling molecular mechanisms toward developing new crop improvement strategies.
Topics: Arabidopsis; Arabidopsis Proteins; Biological Phenomena; Cyclopentanes; Gene Expression Regulation, Plant; Indoleacetic Acids; Oxylipins; Plant Growth Regulators; Transcription Factors
PubMed: 37543224
DOI: 10.1016/j.plantsci.2023.111816 -
Frontiers in Pharmacology 2023
PubMed: 38125891
DOI: 10.3389/fphar.2023.1342596 -
Scientific Reports Aug 2023Integration of the omics data, including metabolomics and proteomics, provides a unique opportunity to search for new associations within metabolic disorders, including...
Integration of plasma and CSF metabolomics with CSF proteomic reveals novel associations between lipid mediators and central nervous system vascular and energy metabolism.
Integration of the omics data, including metabolomics and proteomics, provides a unique opportunity to search for new associations within metabolic disorders, including Alzheimer's disease. Using metabolomics, we have previously profiled oxylipins, endocannabinoids, bile acids, and steroids in 293 CSF and 202 matched plasma samples from AD cases and healthy controls and identified both central and peripheral markers of AD pathology within inflammation-regulating cytochrome p450/soluble epoxide hydrolase pathway. Additionally, using proteomics, we have identified five cerebrospinal fluid protein panels, involved in the regulation of energy metabolism, vasculature, myelin/oligodendrocyte, glia/inflammation, and synapses/neurons, affected in AD, and reflective of AD-related changes in the brain. In the current manuscript, using metabolomics-proteomics data integration, we describe new associations between peripheral and central lipid mediators, with the above-described CSF protein panels. Particularly strong associations were observed between cytochrome p450/soluble epoxide hydrolase metabolites, bile acids, and proteins involved in glycolysis, blood coagulation, and vascular inflammation and the regulators of extracellular matrix. Those metabolic associations were not observed at the gene-co-expression level in the central nervous system. In summary, this manuscript provides new information regarding Alzheimer's disease, linking both central and peripheral metabolism, and illustrates the necessity for the "omics" data integration to uncover associations beyond gene co-expression.
Topics: Humans; Alzheimer Disease; Epoxide Hydrolases; Proteomics; Central Nervous System; Energy Metabolism; Metabolomics; Bile Acids and Salts; Endocannabinoids
PubMed: 37612324
DOI: 10.1038/s41598-023-39737-8 -
Hypertension (Dallas, Tex. : 1979) Mar 2024Small arteries exhibit resting tone, a partially contracted state that maintains arterial blood pressure. In arterial smooth muscle cells, potassium channels control...
BACKGROUND
Small arteries exhibit resting tone, a partially contracted state that maintains arterial blood pressure. In arterial smooth muscle cells, potassium channels control contraction and relaxation. Perivascular adipose tissue (PVAT) has been shown to exert anticontractile effects on the blood vessels. However, the mechanisms by which PVAT signals small arteries, and their relevance remain largely unknown. We aimed to uncover key molecular components in adipose-vascular coupling.
METHODS
A wide spectrum of genetic mouse models targeting , , and genes (, , , , /, and /), telemetry blood pressure measurements, targeted lipidomics, RNA-Seq profiling, wire-myography, patch-clamp, and sharp-electrode membrane potential measurements was used.
RESULTS
We show that PVAT causes smooth muscle cell K7.5 family of voltage-gated potassium (K) channels to hyperpolarize the membrane potential. This effect relaxes small arteries and regulates blood pressure. Oxygenation of polyunsaturated fats generates oxylipins, a superclass of lipid mediators. We identified numerous oxylipins released by PVAT, which potentiate vasodilatory action in small arteries by opening smooth muscle cell K7.5 family of voltage-gated potassium (K) channels.
CONCLUSIONS
Our results reveal a key molecular function of the K7.5 family of voltage-gated potassium (K) channels in the adipose-vascular coupling, translating PVAT signals, particularly oxylipins, to the central physiological function of vasoregulation. This novel pathway opens new therapeutic perspectives.
Topics: Animals; Mice; Adipose Tissue; KCNQ Potassium Channels; Oxylipins; Potassium; Vasodilation
PubMed: 38354270
DOI: 10.1161/HYPERTENSIONAHA.123.21834 -
The American Journal of Clinical... Sep 2023Long-chain polyunsaturated fatty acids (LCPUFAs) and their metabolites are closely related to neovascular eye diseases. However, the clinical significance of their...
BACKGROUND
Long-chain polyunsaturated fatty acids (LCPUFAs) and their metabolites are closely related to neovascular eye diseases. However, the clinical significance of their oxylipins in retinal vein occlusion (RVO) remains inconclusive.
OBJECTIVES
This case-control study aimed to explore metabolomic profiles of LCPUFA oxidation in RVO and to identify potential indicators for diagnosis and pathologic progression.
METHODS
The plasma concentrations of ω-3 (n-3) and ω-6 (n-6) LCPUFA and their oxylipins in 44 adults with RVO and 36 normal controls were analyzed using ultraperformance liquid chromatography tandem mass spectrometry. Univariate analysis combined with principal component and orthogonal projections to latent structure discriminant analysis was used to screen differential metabolites. Aortic ring and choroidal explant sprouting assays were used to investigate the effects of 5-oxo-eicosatetraenoic acids (ETE) on angiogenesis ex vivo. Tubule formation and wound healing assays were performed to verify its effects on human retinal microvascular endothelial cell functions.
RESULTS
Higher ω-6 and lower ω-3 LCPUFA plasma concentrations were measured in the adults with RVO compared with control (odds ratio [OR]: 2.34; 95% confidence interval [CI]: 1.42, 3.86; P < 0.001; OR: 0.28; 95% CI: 0.15, 0.51; P < 0.001). Metabolomic analysis revealed 20 LCPUFA and their oxylipins dysregulated in RVO, including increased arachidonic acid (ω-6, OR: 1.85; 95% CI: 1.18, 2.90; P < 0.001) and its lipoxygenase product 5-oxo-ETE (OR: 11.76; 95% CI: 3.73, 37.11; P < 0.001), as well as decreased docosahexaenoic acid (ω-3, OR: 0.13; 95% CI: 0.05, 0.33; P < 0.001). Interestingly, 5-oxo-ETE was downregulated in ischemic compared with nonischemic central RVO. Exogenous 5-oxo-ETE attenuated aortic ring and choroidal explant sprouting and inhibited tubule formation and migration of human retinal microvascular endothelial cells in a dose-dependent manner, possibly via suppressing the vascular endothelial growth factor signaling pathway.
CONCLUSIONS
The plasma concentrations of ω-6 and ω-3 LCPUFA and their oxylipins were associated with RVO. The ω-6 LCPUFA-derived metabolite 5-oxo-ETE was a potential marker of RVO development and progression.
Topics: Humans; Adult; Retinal Vein Occlusion; Endothelial Cells; Case-Control Studies; Oxylipins; Vascular Endothelial Growth Factor A; Fatty Acids, Omega-3
PubMed: 37454758
DOI: 10.1016/j.ajcnut.2023.07.006 -
Prostaglandins & Other Lipid Mediators Apr 2024Uncontrolled or dysregulated inflammation has adverse effects on the reproduction, production and health of animals, and is a major pathological cause of increased... (Review)
Review
Uncontrolled or dysregulated inflammation has adverse effects on the reproduction, production and health of animals, and is a major pathological cause of increased incidence and severity of infectious and metabolic diseases. To achieve successful transition from a non-lactation pregnant state to a non-pregnant lactation state, drastic metabolic and endocrine alteration have taken place in dairy cows during the periparturient period. These physiological changes, coupled with decreased dry matter intake near calving and sudden change of diet composition after calving, have the potential to disrupt the delicate balance between pro- and anti-inflammation, resulting in a disordered or excessive inflammatory response. In addition to cytokines and other immunoregulatory factors, most oxylipins formed from polyunsaturated fatty acids (PUFAs) via enzymatic and nonenzymatic oxygenation pathways have pro- or anti-inflammatory properties and play a pivotal role in the onset, development and resolution of inflammation. However, little attention has been paid to the possibility that oxylipins could function as endogenous immunomodulating agents. This review will provide a detailed overview of the main oxylipins derived from different PUFAs and discuss the regulatory role that oxylipins play in the postpartum inflammatory response in dairy cows. Based on the current research, much remains to be illuminated in this emerging field. Understanding the role that oxylipins play in the control of postpartum inflammation and inflammatory-based disease may improve our ability to prevent transition disorders via Management, pharmacological, genetic selection and dietary intervention strategies.
Topics: Female; Humans; Pregnancy; Cattle; Animals; Oxylipins; Energy Metabolism; Postpartum Period; Lactation; Inflammation; Diet; Fatty Acids, Unsaturated; Anti-Inflammatory Agents; Milk
PubMed: 38280540
DOI: 10.1016/j.prostaglandins.2024.106814 -
The Journal of Physiology Dec 2023Our laboratory previously showed lipid hydroperoxides and oxylipin levels are elevated in response to loss of skeletal muscle innervation and are associated with muscle...
Our laboratory previously showed lipid hydroperoxides and oxylipin levels are elevated in response to loss of skeletal muscle innervation and are associated with muscle pathologies. To elucidate the pathological impact of lipid hydroperoxides, we overexpressed glutathione peroxidase 4 (GPx4), an enzyme that targets reduction of lipid hydroperoxides in membranes, in adult CuZn superoxide dismutase knockout (Sod1KO) mice that show accelerated muscle atrophy associated with loss of innervation. The gastrocnemius muscle from Sod1KO mice shows reduced mitochondrial respiration and elevated oxidative stress (F -isoprostanes and hydroperoxides) compared to wild-type (WT) mice. Overexpression of GPx4 improved mitochondrial respiration and reduced hydroperoxide generation in Sod1KO mice, but did not attenuate the muscle loss that occurs in Sod1KO mice. In contrast, contractile force generation is reduced in EDL muscle in Sod1KO mice relative to WT mice, and overexpression of GPx4 restored force generation to WT levels in Sod1KO mice. GPx4 overexpression also prevented loss of muscle contractility at the single fibre level in fast-twitch fibres from Sod1KO mice. Muscle fibres from Sod1KO mice were less sensitive to both depolarization and calcium at the single fibre level and exhibited a reduced activation by S-glutathionylation. GPx4 overexpression in Sod1KO mice rescued the deficits in both membrane excitability and calcium sensitivity of fast-twitch muscle fibres. Overexpression of GPx4 also restored the sarco/endoplasmic reticulum Ca -ATPase activity in Sod1KO gastrocnemius muscles. These data suggest that GPx4 plays an important role in preserving excitation-contraction coupling function and Ca homeostasis, and in maintaining muscle and mitochondrial function in oxidative stress-induced sarcopenia. KEY POINTS: Knockout of CuZn superoxide dismutase (Sod1KO) induces elevated oxidative stress with accelerated muscle atrophy and weakness. Glutathione peroxidase 4 (GPx4) plays a fundamental role in the reduction of lipid hydroperoxides in membranes, and overexpression of GPx4 improves mitochondrial respiration and reduces hydroperoxide generation in Sod1KO mice. Muscle contractile function deficits in Sod1KO mice are alleviated by the overexpression of GPx4. GPx4 overexpression in Sod1KO mice rescues the impaired muscle membrane excitability of fast-twitch muscle fibres and improves their calcium sensitivity. Sarco/endoplasmic reticulum Ca -ATPase activity in Sod1KO muscles is decreased, and it is restored by the overexpression of GPx4. Our results confirm that GPx4 plays an important role in preserving excitation-contraction coupling function and Ca homeostasis, and maintaining muscle and mitochondrial function in oxidative stress-induced sarcopenia.
Topics: Animals; Mice; Adenosine Triphosphatases; Calcium; Glutathione; Glutathione Peroxidase; Hydrogen Peroxide; Lipids; Mice, Knockout; Muscle, Skeletal; Phenotype; Phospholipid Hydroperoxide Glutathione Peroxidase; Sarcopenia; Superoxide Dismutase; Superoxide Dismutase-1
PubMed: 37878529
DOI: 10.1113/JP285259