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Rheumatology (Oxford, England) Mar 2022In pre-clinical studies, pinolenic acid (PNLA), an omega-6-polyunsaturated fatty acid from pine nuts, has shown anti-inflammatory effects. We aimed to investigate the...
OBJECTIVES
In pre-clinical studies, pinolenic acid (PNLA), an omega-6-polyunsaturated fatty acid from pine nuts, has shown anti-inflammatory effects. We aimed to investigate the effect of PNLA in human cell lines and peripheral blood mononuclear cells (PBMCs) from RA patients and healthy controls (HCs).
METHODS
A modified Boyden chamber was used to assess chemokine-induced migration of THP-1 monocytes. Macropinocytosis was assessed using Lucifer yellow and oxidized low-density lipoprotein (oxLDL) uptake using DiI-labelled oxLDL in THP-1 macrophages and human monocyte-derived macrophages (HMDMs). IL-6, TNF-α and prostaglandin E2 (PGE2) release by lipopolysaccharide (LPS)-stimulated PBMCs from RA patients and HCs was measured by ELISA. The transcriptomic profile of PNLA-treated, LPS-activated PBMCs was investigated by RNA-sequencing.
RESULTS
PNLA reduced THP-1 cell migration by 55% (P < 0.001). Macropinocytosis and DiI-oxLDL uptake were reduced by 50% (P < 0.001) and 40% (P < 0.01), respectively, in THP-1 macrophages and 40% (P < 0.01) and 25% (P < 0.05), respectively, in HMDMs. PNLA reduced IL-6 and TNF-α release from LPS-stimulated PBMCs from RA patients by 60% (P < 0.001) and from HCs by 50% and 35%, respectively (P < 0.01). PNLA also reduced PGE2 levels in such PBMCs from RA patients and HCs (P < 0.0001). Differentially expressed genes whose expression was upregulated included pyruvate dehydrogenase kinase-4, plasminogen activator inhibitor-1, fructose bisphosphatase1 and N-Myc downstream-regulated gene-2, which have potential roles in regulating immune and metabolic pathways. Pathway analysis predicted upstream activation of the nuclear receptors peroxisome proliferator-activated receptors involved in anti-inflammatory processes, and inhibition of nuclear factor-κB and signal transducer and activator of transcription 1.
CONCLUSIONS
PNLA has immune-metabolic effects on monocytes and PBMCs that are pathogenic in RA and atherosclerosis. Dietary PNLA supplementation may be beneficial in RA.
Topics: Arthritis, Rheumatoid; Case-Control Studies; Cell Movement; Dinoprostone; Gene Expression Profiling; Humans; Interleukin-6; Leukocytes, Mononuclear; Linolenic Acids; Lipoproteins, LDL; Macrophages; THP-1 Cells; Tumor Necrosis Factor-alpha
PubMed: 34080609
DOI: 10.1093/rheumatology/keab467 -
The Journal of Biological Chemistry Jan 1985The metabolism of columbinic acid by various fatty acid oxidizing enzyme systems was studied. A cyclooxygenase product, 9-hydroxy-(5E,10E,12Z)-octadecatrienoic acid, was...
The metabolism of columbinic acid by various fatty acid oxidizing enzyme systems was studied. A cyclooxygenase product, 9-hydroxy-(5E,10E,12Z)-octadecatrienoic acid, was formed nearly quantitatively by ram seminal vesicle microsomes and in small amounts by washed human platelets. The major lipoxygenase product from washed human platelets, soybean lipoxygenase, and neonatal rat epidermal homogenate was 13-hydroxy-(5E,9Z,11E)-octadecatrienoic acid, although lesser quantities of other isomers differing in the double bond configurations were also identified by ultraviolet spectrophotometry and gas chromatography-mass spectroscopy. Topical application of the major lipoxygenase product to paws of essential fatty acid-deficient rats resulted in nearly as complete resolution of the scaly dermatitis as did the application of columbinic acid itself; the cyclooxygenase product was not at all effective.
Topics: 3-Hydroxyacyl CoA Dehydrogenases; Acetyl-CoA C-Acyltransferase; Administration, Topical; Animals; Blood Platelets; Carbon-Carbon Double Bond Isomerases; Chromatography, High Pressure Liquid; Enoyl-CoA Hydratase; Fatty Acids, Essential; Humans; Linolenic Acids; Lipoxygenase; Male; Multienzyme Complexes; Prostaglandin-Endoperoxide Synthases; Racemases and Epimerases; Rats; Seminal Vesicles; Sheep; Skin; Skin Diseases
PubMed: 3918037
DOI: No ID Found -
Scientific Reports May 2022Pinolenic acid (PNLA), an omega-6 polyunsaturated fatty acid from pine nuts, has anti-inflammatory and anti-atherogenic effects. We aimed to investigate the direct...
Pinolenic acid (PNLA), an omega-6 polyunsaturated fatty acid from pine nuts, has anti-inflammatory and anti-atherogenic effects. We aimed to investigate the direct anti-inflammatory effect and anti-atherogenic effects of PNLA on activated purified CD14 monocytes from peripheral blood of patients with rheumatoid arthritis (RA) in vitro. Flow cytometry was used to assess the proportions of CD14 monocytes expressing TNF-α, IL-6, IL-1β, and IL-8 in purified monocytes from patients with RA after lipopolysaccharide (LPS) stimulation with/without PNLA pre-treatment. The whole genomic transcriptome (WGT) profile of PNLA-treated, and LPS-activated monocytes from patients with active RA was investigated by RNA-sequencing. PNLA reduced percentage of monocytes expressing cytokines: TNF-α by 23% (p = 0.048), IL-6 by 25% (p = 0.011), IL-1β by 23% (p = 0.050), IL-8 by 20% (p = 0.066). Pathway analysis identified upstream activation of peroxisome proliferator-activated receptors (PPARs), sirtuin3, and let7 miRNA, and KLF15, which are anti-inflammatory and antioxidative. In contrast, DAP3, LIF and STAT3, which are involved in TNF-α, and IL-6 signal transduction, were inhibited. Canonical Pathway analysis showed that PNLA inhibited oxidative phosphorylation (p = 9.14E-09) and mitochondrial dysfunction (p = 4.18E-08), while the sirtuin (SIRTs) signalling pathway was activated (p = 8.89E-06) which interfere with the pathophysiological process of atherosclerosis. Many miRNAs were modulated by PNLA suggesting potential post-transcriptional regulation of metabolic and immune response that has not been described previously. Multiple miRNAs target pyruvate dehydrogenase kinase-4 (PDK4), single-immunoglobulin interleukin-1 receptor molecule (SIGIRR), mitochondrially encoded ATP synthase membrane subunit 6 (MT-ATP6) and acetyl-CoA acyltranferase2 (ACAA2); genes implicated in regulation of lipid and cell metabolism, inflammation, and mitochondrial dysfunction. PNLA has potential anti-atherogenic and immune-metabolic effects on monocytes that are pathogenic in RA and atherosclerosis. Dietary PNLA supplementation regulates key miRNAs that are involved in metabolic, mitochondrial, and inflammatory pathways.
Topics: Anti-Inflammatory Agents; Arthritis, Rheumatoid; Atherosclerosis; Cells, Cultured; Cytokines; Humans; Interleukin-6; Interleukin-8; Linolenic Acids; Lipopolysaccharides; MicroRNAs; Monocytes; Tumor Necrosis Factor-alpha
PubMed: 35614190
DOI: 10.1038/s41598-022-12763-8 -
International Journal of Molecular... Jan 2023Inflammatory disorders such as atherosclerosis, diabetes and rheumatoid arthritis are regulated by cytokines and other inflammatory mediators. Current treatments for... (Review)
Review
Inflammatory disorders such as atherosclerosis, diabetes and rheumatoid arthritis are regulated by cytokines and other inflammatory mediators. Current treatments for these conditions are associated with significant side effects and do not completely suppress inflammation. The benefits of diet, especially the role of specific components, are poorly understood. Polyunsaturated fatty acids (PUFAs) have several beneficial health effects. The majority of studies on PUFAs have been on omega-3 fatty acids. This review will focus on a less studied fatty acid, pinolenic acid (PNLA) from pine nuts, which typically constitutes up to 20% of its total fatty acids. PNLA is emerging as a dietary PUFA and a promising supplement in the prevention of inflammatory disorders or as an alternative therapy. Some studies have shown the health implications of pine nuts oil (PNO) and PNLA in weight reduction, lipid-lowering and anti-diabetic actions as well as in suppression of cell invasiveness and motility in cancer. However, few reviews have specifically focused on the biological and anti-inflammatory effects of PNLA. Furthermore, in recent bioinformatic studies on human samples, the expression of many mRNAs and microRNAs was regulated by PNLA indicating potential transcriptional and post-transcriptional regulation of inflammatory and metabolic processes. The aim of this review is to summarize, highlight, and evaluate research findings on PNO and PNLA in relation to potential anti-inflammatory benefits and beneficial metabolic changes. In this context, the focus of the review is on the potential actions of PNLA on inflammation along with modulation of lipid metabolism and oxidative stress based on data from both in vitro and in vivo experiments, and human findings, including gene expression analysis.
Topics: Humans; Nuts; Inflammation; Linolenic Acids; Fatty Acids, Unsaturated; Anti-Inflammatory Agents; Fatty Acids, Omega-3
PubMed: 36674687
DOI: 10.3390/ijms24021171 -
The British Journal of Nutrition Jun 2015Various foods are associated with effects against metabolic diseases such as insulin resistance and type 2 diabetes; however, their mechanisms of action are mostly...
Various foods are associated with effects against metabolic diseases such as insulin resistance and type 2 diabetes; however, their mechanisms of action are mostly unclear. Fatty acids may contribute by acting as precursors of signalling molecules or by direct activity on receptors. The medium- and long-chain NEFA receptor FFA1 (free fatty acid receptor 1, previously known as GPR40) has been linked to enhancement of glucose-stimulated insulin secretion, whereas FFA4 (free fatty acid receptor 4, previously known as GPR120) has been associated with insulin-sensitising and anti-inflammatory effects, and both receptors are reported to protect pancreatic islets and promote secretion of appetite and glucose-regulating hormones. Hypothesising that FFA1 and FFA4 mediate therapeutic effects of dietary components, we screened a broad selection of NEFA on FFA1 and FFA4 and characterised active compounds in concentration-response curves. Of the screened compounds, pinolenic acid, a constituent of pine nut oil, was identified as a relatively potent and efficacious dual FFA1/FFA4 agonist, and its suitability for further studies was confirmed by additional in vitro characterisation. Pine nut oil and free and esterified pure pinolenic acid were tested in an acute glucose tolerance test in mice. Pine nut oil showed a moderately but significantly improved glucose tolerance compared with maize oil. Pure pinolenic acid or ethyl ester gave robust and highly significant improvements of glucose tolerance. In conclusion, the present results indicate that pinolenic acid is a comparatively potent and efficacious dual FFA1/FFA4 agonist that exerts antidiabetic effects in an acute mouse model. The compound thus deserves attention as a potential active dietary ingredient to prevent or counteract metabolic diseases.
Topics: Animals; Diabetes Mellitus, Type 2; Dietary Fats; Disease Models, Animal; Glucose Tolerance Test; HEK293 Cells; Humans; Insulin; Insulin Resistance; Insulin Secretion; Islets of Langerhans; Linolenic Acids; Male; Metabolic Syndrome; Mice; Mice, Inbred C57BL; Nuts; Pinus; Receptors, G-Protein-Coupled
PubMed: 25916176
DOI: 10.1017/S000711451500118X -
Applied Microbiology and Biotechnology Aug 2009Lactobacillus plantarum AKU 1009a effectively transforms linoleic acid to conjugated linoleic acids of cis-9,trans-11-octadecadienoic acid (18:2) and...
Lactobacillus plantarum AKU 1009a effectively transforms linoleic acid to conjugated linoleic acids of cis-9,trans-11-octadecadienoic acid (18:2) and trans-9,trans-11-18:2. The transformation of various polyunsaturated fatty acids by washed cells of L. plantarum AKU 1009a was investigated. Besides linoleic acid, alpha-linolenic acid [cis-9,cis-12,cis-15-octadecatrienoic acid (18:3)], gamma-linolenic acid (cis-6,cis-9,cis-12-18:3), columbinic acid (trans-5,cis-9,cis-12-18:3), and stearidonic acid [cis-6,cis-9,cis-12,cis-15-octadecatetraenoic acid (18:4)] were found to be transformed. The fatty acids transformed by the strain had the common structure of a C18 fatty acid with the cis-9,cis-12 diene system. Three major fatty acids were produced from alpha-linolenic acid, which were identified as cis-9,trans-11,cis-15-18:3, trans-9,trans-11,cis-15-18:3, and trans-10,cis-15-18:2. Four major fatty acids were produced from gamma-linolenic acid, which were identified as cis-6,cis-9,trans-11-18:3, cis-6,trans-9,trans-11-18:3, cis-6,trans-10-18:2, and trans-10-octadecenoic acid. The strain transformed the cis-9,cis-12 diene system of C18 fatty acids into conjugated diene systems of cis-9,trans-11 and trans-9,trans-11. These conjugated dienes were further saturated into the trans-10 monoene system by the strain. The results provide valuable information for understanding the pathway of biohydrogenation by anaerobic bacteria and for establishing microbial processes for the practical production of conjugated fatty acids, especially those produced from alpha-linolenic acid and gamma-linolenic acid.
Topics: Biotransformation; Fatty Acids; Fatty Acids, Unsaturated; Hydrogenation; Lactobacillus plantarum; Linoleic Acids, Conjugated; alpha-Linolenic Acid
PubMed: 19319523
DOI: 10.1007/s00253-009-1949-0 -
Journal of Oleo Science 2018Δ5-Olefinic acids have been characterized in gymnosperm plants and have been reported to have several biological health benefits. Δ5-Olefinic acids from pine nut oil...
Δ5-Olefinic acids have been characterized in gymnosperm plants and have been reported to have several biological health benefits. Δ5-Olefinic acids from pine nut oil were effectively concentrated by repeated lipase-catalyzed esterification. The pine nut oil contained three major Δ5-olefinic acids, namely taxoleic acid (C18:2 Δ5,9), pinolenic acid (C18:3 Δ5,9,12), and sciadonic acid (C20:3 Δ5,11,14). The fatty acids present in pine nut oil were selectively esterified with ethanol using Lipozyme RM IM from Rhizomucor miehei as a biocatalyst. The Δ5-olefinic acids were concentrated in the unesterified fatty acid fraction. The optimum molar ratio of the substrates (fatty acid:ethanol), temperature, the enzyme loading, and the reaction time were 1:7, 25°C, 5% of total substrate weight, and 6 h, respectively. There was no significant effect in the concentration of Δ5-olefinic acids when water was added in the reaction mixture. The same protocol and optimum conditions were employed for two times repeated lipase-catalyzed esterifications. In first lipase-catalyzed esterification, the Δ5-olefinic acids content in the pine nut oil increased from 17 mol% to 51 mol% with a yield of 40 mol%. In a second lipase-catalyzed esterification, with the Δ5-olefinic acids-concentrated fatty acids obtained from the first reaction as the substrate, the Δ5-olefinic acids content increased to 86 mol% with a yield of 15 mol%. Finally, a maximum Δ5-olefinic acids content of ca. 96 mol% with a yield of 6 mol% was obtained via a third lipase-catalyzed esterification.
Topics: Alkenes; Arachidonic Acids; Biocatalysis; Chemistry, Organic; Esterification; Ethanol; Linolenic Acids; Lipase; Nuts; Pinus; Plant Oils; Rhizomucor; Temperature
PubMed: 30404964
DOI: 10.5650/jos.ess18136 -
The Plant Cell May 2019Endoplasmic reticulum (ER) stress is caused by the stress-induced accumulation of unfolded proteins in the ER. Here, we identified proteins and lipids that function...
Endoplasmic reticulum (ER) stress is caused by the stress-induced accumulation of unfolded proteins in the ER. Here, we identified proteins and lipids that function downstream of the ER stress sensor INOSITOL-REQUIRING ENZYME1 (CrIRE1) that contributes to ER stress tolerance in Chlamydomonas (). Treatment with the ER stress inducer tunicamycin resulted in the splicing of a 32-nucleotide fragment of a basic leucine zipper 1 (bZIP1) transcription factor () mRNA by CrIRE1 that, in turn, resulted in the loss of the transmembrane domain in CrbZIP1, and the translocation of CrbZIP1 from the ER to the nucleus. Mutants deficient in failed to induce the expression of the unfolded protein response genes and grew poorly under ER stress. Levels of diacylglyceryltrimethylhomoserine (DGTS) and pinolenic acid (18:3Δ5,9,12) increased in the parental strains but decreased in the mutants under ER stress. A yeast one-hybrid assay revealed that CrbZIP1 activated the expression of enzymes catalyzing the biosynthesis of DGTS and pinolenic acid. Moreover, two lines harboring independent mutant alleles of () failed to synthesize pinolenic acid and were more sensitive to ER stress than were their parental lines. Together, these results indicate that is a critical component of the ER stress response mediated by CrIRE1 in Chlamydomonas that acts via lipid remodeling.
Topics: Alleles; Basic-Leucine Zipper Transcription Factors; Cell Nucleus; Chlamydomonas reinhardtii; Endoplasmic Reticulum; Endoplasmic Reticulum Stress; Linolenic Acids; Lipid Metabolism; Mutation; Plant Proteins; RNA, Messenger; RNA, Plant; Triglycerides; Tunicamycin; Unfolded Protein Response
PubMed: 30894460
DOI: 10.1105/tpc.18.00723 -
The Journal of Investigative Dermatology Aug 1992We showed previously that the activity of 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase, the rate-limiting enzyme of cholesterol biosynthesis, increases...
We showed previously that the activity of 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase, the rate-limiting enzyme of cholesterol biosynthesis, increases after both barrier disruption with organic solvents and in essential fatty acid deficiency (EFAD). Here, we treated EFAD hairless mice with linoleic acid, columbinic acid (C18: 3, n-6, trans; not metabolizable to known regulatory eicosanoids), prostaglandin E2 (PGE2), or latex occlusion, and determined transepidermal water loss (TEWL), epidermal protein content, and epidermal HMG CoA reductase activity. Increased TEWL rates in EFAD were accompanied by increased HMG CoA reductase activity (+130%, n = 6, p less than 0.01) and protein content (+69%; n = 6, p less than 0.025). Artificial restoration of the barrier by occlusion reduced the increase in enzyme activity and protein content toward normal, but barrier function, measured immediately after removal of the latex wrap, deteriorated further (TEWL: two-fold greater than EFAD unoccluded; p less than 0.01). Topical applications of either linoleate or columbinate (but not PGE2), normalized barrier function, HMG CoA reductase activity, and protein content. These results show that a) barrier function modulates HMG CoA reductase activity; b) reduction of cholesterol synthesis with occlusion results in a further deterioration in barrier function, suggesting that increased synthesis is a protective homeostatic response; and c) the barrier abnormality reflects a requirement for specific fatty acids for the barrier rather than resulting from epidermal hyperplasia or decreased prostaglandin generation.
Topics: Animals; Cell Membrane Permeability; Cholesterol; Eicosanoids; Epidermis; Fatty Acids, Essential; Hydroxymethylglutaryl CoA Reductases; Hyperplasia; Male; Mice; Mice, Hairless; Skin
PubMed: 1629633
DOI: 10.1111/1523-1747.ep12650440 -
Journal of Oleo Science 2018Pinolenic acid (PLA), which is a fatty acid (FA) exclusively found in the oils of edible pine nuts, has an appetite-suppression effect, thereby being effective to reduce...
Pinolenic acid (PLA), which is a fatty acid (FA) exclusively found in the oils of edible pine nuts, has an appetite-suppression effect, thereby being effective to reduce body weight in humans. PLA concentrates would be suitable for use in functional foods and nutraceuticals due to the health benefits of PLA. PLA concentrates were prepared from free FA (FFA) obtained from pine nut oil using solvent fractionation. Siberian pine nut oil containing 18.3 wt% PLA was used as the starting material for the fractionation. The fractionation was performed in n-hexane at ultra-low temperatures down to -85°C. The PLA concentrates produced under the optimal conditions established in this study (temperature, -85°C; n-hexane-to-FFA ratio (v/w), 30:1; fractionation time, 36 h) contained 69.8 wt% PLA. The yield of PLA was 77.4 wt% of the initial PLA weight in the FFA. These results suggest that solvent fractionation is a more effective approach to prepare PLA concentrates with higher PLA contents at a particular yield of PLA than published methods using urea crystallization (e.g., PLA content = ~47 wt%, yield of PLA = ~77 wt%, Woo et al. (2016)) or lipase-catalyzed reactions (e.g., PLA content = ~30 wt%, yield of PLA = ~61 wt%, Lee et al. (2011)). The resulting PLA concentrates contained 11 of the 12 different species of FA present in the FFA, thereby indicating that the PLA concentrates prepared by solvent fractionation have more diverse FA profiles than those prepared by urea crystallization (e.g., 7 species of FA, Woo et al. (2016)).
Topics: Appetite Depressants; Chemical Fractionation; Cold Temperature; Fatty Acids, Nonesterified; Hexanes; Linolenic Acids; Nuts; Pinus; Plant Oils; Solvents
PubMed: 30404957
DOI: 10.5650/jos.ess18100