Non-esterified erythrocyte linoleic acid, arachidonic acid, and subjective sleep outcomes.

OBJECTIVE: This study investigated whether non-esterified erythrocyte omega-6 PUFAs were associated with subjective assessment of sleep quality and duration, and risk for obstructive sleep apnea. METHODS: In this secondary analysis of the cross-sectional OPPERA-II study, 538 adults completed the Pittsburgh Sleep Quality Index (PSQI), reported their usual hours of sleep, and answered STOP screening questions for obstructive sleep apnea. Circulating non-esterified erythrocyte concentrations of omega-6 PUFA linoleic acid and arachidonic acid were quantified by liquid chromatography tandem mass spectroscopy. Sleep outcomes were dichotomized as poor (PSQI ≤5) vs good (PSQI ≥6) sleep quality, insufficient or excessive (≤6 or >9 h) vs good (7-9 h) sleep duration, and high (≥2 affirmative responses) vs low (<2 affirmative responses) risk for obstructive sleep apnea. Non-esterified omega-6 PUFAs and the continuous covariates of body mass index, Short Form (SF) 12 Health Survey Physical and Mental Component scores and resting measures of systolic and diastolic blood pressure were standardized for multivariable analysis. Categorical covariates were study site, age, sex, and race/ethnicity. Multivariable-adjusted logistic regression first estimated odds ratios (OR) and 95% confidence limits (CL) for sleep outcomes using linoleic acid as the main exposure. Analysis was then repeated using arachidonic acid as the main exposure. RESULTS: In the multivariable-adjusted model, each standard deviation increase in non-esterified erythrocyte linoleic acid was associated with higher odds of poor sleep quality (OR=1.2, 95% CL: 1.1, 1.5), insufficient or excessive sleep (OR= 1.3, 95% CL: 1.1, 1.6) and high-risk for obstructive sleep apnea (OR=1.3, 95% CL: 1.1, 1.6). Likewise, for each standard deviation increase in non-esterified erythrocyte arachidonic acid, odds increased of poor sleep quality (OR=1.2, 95% CL: 1.1, 1.5), and insufficient or excessive sleep (OR=1.2, 95% CL: 1.1, 1.5). Odds of being high risk for obstructive sleep apnea increased with greater circulating arachidonic acid, but the association did not reach statistical significance (OR=1.1, 95% CL: 0.9, 1.4). CONCLUSION: Non-esterified erythrocyte linoleic acid and arachidonic acid were associated with poor sleep quality and insufficient or excessive sleep duration. Linoleic acid, but not arachidonic acid, was also associated with high risk for obstructive sleep apnea.

Circulating Polyunsaturated Fatty Acids and Pain Intensity in Five Chronic Pain Conditions.

Pain intensity is well-known to be influenced by a wide range of biobehavioral variables. Nutritional factors, however, have not been generally considered for their potential importance. This cross-sectional study examined associations between erythrocyte omega-6 (n-6) and omega-3 (n-3) polyunsaturated fatty acids (PUFAs) and pain intensity in 605 adults. Pain intensity was computed on a 0 to 100 numeric rating scale from questions about 5 chronic pain conditions: orofacial pain, headache, low back pain, irritable bowel syndrome, and bodily pain. For each pain condition, multiple linear regression tested the hypothesis that a higher ratio of n-6 arachidonic acid to the sum of n-3 eicosapentaenoic acid and docosahexaenoic acid (AA/(EPA+DHA) was associated with greater pain intensity. In covariate-adjusted analysis, orofacial pain intensity increased 5.7 points (95% CI: 1.4, 9.9) per unit increase in n-6/n-3 PUFA ratio. Likewise, a 1 unit increase in n-6/n-3 PUFA ratio was associated with significant increases in pain intensity (range 5-8 points) of headache pain, low back pain, and bodily pain, but not abdominal pain. Separate multiple linear regression models investigated the independent strength of association of individual PUFAs to the intensity of each pain condition. Overall, n-3 docosahexaenoic acid was most strongly, and inversely, associated with pain intensity. PERSPECTIVE: A higher ratio of n-6/n-3 long-chain polyunsaturated fatty acids was associated greater pain intensity for orofacial pain, headache, low back pain, and bodily pain, but not abdominal pain. The n-6/n-3 PUFA ratio was more consistently associated with pain intensity than any individual constituent of the long-chain PUFA ratio.

Dataset linking free polyunsaturated fatty acid concentrations in erythrocytes with chronic pain conditions in adults.

Circulating polyunsaturated fatty acids (PUFAs) and lipid mediators were extracted from human red blood cells and quantified using liquid chromatography-tandem mass spectrometry (LC-MS/MS). The method encompassed 13 different PUFAs and lipid mediators, however, due to instrument capability only five were confidently quantified (EPA, ALA, AA, DHA, and LA). The extraction focused on free polyunsaturated fatty acids since they have a strong correlation with health in humans. The study design was a secondary analysis of the OPPERA-2 study of chronic overlapping pain conditions in adults. The data included are: a) raw LC-MS/MS data (.raw); b) processed data (.xlsx) including chromatographic peak area for each compound and a concentration (ng/mL) based on external calibration with internal standardization using pure analytical grade standards and heavy-isotope labeled internal standards; c) study participant demographics and phenotypes (.xlsx). This dataset consisting of circulating PUFA quantities measured in 605 humans has been made publicly available for analysis and interpretation.

Circulating polyunsaturated fatty acids, pressure pain thresholds, and nociplastic pain conditions.

OBJECTIVE: Polyunsaturated fatty acids (PUFAs) play a role in pain regulation. This study sought to determine whether free PUFAs found in red blood cells also play a role in nociceptive processing. We examined associations between circulating PUFAs and nociceptive thresholds to noxious mechanical stimuli. We also determined whether nociceptive thresholds were associated with nociplastic pain conditions. METHODS: This cross-sectional study used stored red bloods cells and data from 605 adult participants in the OPPERA-2 study of chronic overlapping pain conditions. In OPPERA-2 adults completed quantitative sensory testing in which pressure algometry measured deep muscular tissue sensitivity at six anatomical sites. Standardized protocols classified adults for presence or absence of five nociplastic pain conditions: temporomandibular disorder, headache, low back pain, irritable bowel syndrome and fibromyalgia. Liquid chromatography tandem mass spectroscopy quantified erythrocyte PUFAs. We conducted three sets of analyses. First, a multivariable linear regression model assessed the association between n-6/n-3 PUFA ratio and the number of overlapping nociplastic pain conditions. Second, a series of 36 multivariable linear regression models assessed covariate-adjusted associations between PUFAs and nociceptive thresholds at each of six anatomical sites. Third, a series of 30 multivariable linear regression models assessed covariate-adjusted associations between nociceptive thresholds at six anatomical sites and each of five pain conditions. RESULTS: In multiple linear regression, each unit increase in n-6/n-3 PUFA ratio was associated with more pain conditions (ß = 0.30, 95% confidence limits: 0.07, 0.53, p = 0.012). Omega-6 linoleic acid and arachidonic acid were negatively associated with lower nociceptive thresholds at three and at five, respectively, anatomical sites. In contrast, omega-3 alpha-linolenic acid, eicosapentaenoic acid, docosahexaenoic acid and the n-6/n-3 PUFA ratio were not associated with nociceptive thresholds at any site. Pain cases had significantly lower nociceptive thresholds than non-case controls at all anatomical sites. CONCLUSION: A higher n-6/n-3 PUFA ratio was associated with more pain conditions. Omega-6 PUFAs may promote a generalized upregulation of nociceptive processing.

Circulating Omega-6 and Omega-3 Polyunsaturated Fatty Acids in Painful Temporomandibular Disorder and Low Back Pain.

Preclinical studies demonstrate opposing effects of long-chain polyunsaturated fatty acid (PUFA) metabolites on inflammation and nociception. Omega-6 (n-6) PUFAs amplify both processes while omega-3 (n-3) PUFAs inhibit them. This cross-sectional study examined relationships between PUFAs in circulating erythrocytes and 2 chronic idiopathic pain conditions: temporomandibular disorder (TMD) and low back pain in a community-based sample of 503 U.S. adults. Presence or absence of TMD and low back pain, respectively, were determined by clinical examination and by responses to established screening questions. Liquid chromatography-tandem mass spectrometry quantified PUFAs. In multivariable logistic regression models, a higher ratio of n-6/n-3 long-chain PUFAs was associated with greater odds of TMD (odds ratio ((OR) = 1.75, 95% confidence limits (CL): 1.16, 2.64) and low back pain (OR = 1.63, 95% CL: 1.07, 2.49). Higher levels of the pronociceptive n-6 long-chain arachidonic acid (AA) were associated with a greater probability of both pain conditions for women, but not men. Higher levels of the antinociceptive long-chain n-3 PUFAs eicosapentaenoic and docosahexaenoic acids were associated with a lower probability of both pain conditions for men, but not women. As systemic inflammation is not a hallmark of these conditions, PUFAs may influence idiopathic pain through other mechanisms. PERSPECTIVE: This cross-sectional clinical study found that a higher ratio of circulating n-6/n-3 long-chain PUFAs was associated with greater odds of 2 common chronic overlapping pain conditions. This suggests that the pro and antinociceptive properties of n-6 and n-3 PUFAs, respectively, influence pain independently of their well-established inflammatory pathways.

Ratio of Omega-6/Omega-3 Polyunsaturated Fatty Acids Associated With Somatic and Depressive Symptoms in People With Painful Temporomandibular Disorder and Irritable Bowel Syndrome.

Somatic symptom disturbance is among the strongest predictors of painful temporomandibular disorder (TMD). Related psychological constructs, such as anxiety and depression, respond therapeutically to omega-3 polyunsaturated fatty acids (PUFAs) in clinical trials. This cross-sectional study investigated associations between the omega-6/omega-3 PUFA ratio and somatic symptom disturbance and depressive symptoms in a community-based sample of 501 adults and determined whether these associations differed between adults with and without TMD or irritable bowel syndrome (IBS). Liquid chromatography tandem mass spectrometry quantified PUFAs in circulating erythrocytes. Somatic symptoms and depression were quantified using Symptom Checklist-90-Revised subscales. Presence or absence of TMD and IBS, respectively, were determined by clinical examination and Rome III screening questions. The standardized beta coefficient for the omega-6/omega-3 long-chain PUFA ratio was 0.26 (95% confidence limits (CL): 0.08, 0.43) in a multivariable linear regression model in which somatic symptom disturbance was the dependent variable. When modelling depressive symptoms as the dependent variable, the standardized beta coefficient was 0.17 (95% CL:0.01, 0.34). Both associations were stronger among TMD cases and IBS cases than among non-cases. Future randomized control trials that lower the omega-6/omega-3 PUFA ratio could consider somatic or depressive symptoms as a therapeutic target for TMD or IBS pain. PERSPECTIVE: In people with TMD or IBS, a high n-6/n-3 PUFA ratio was positively associated with somatic symptom disturbance and depressive symptoms. Both measures of psychological distress were elevated in people with painful TMD and IBS. Future randomized clinical trials will determine whether lowering the n-6/n-3 ratio is therapeutic for pain.

Acyl-Coa Thioesterases: A Rheostat That Controls Activated Fatty Acids Modulates Dengue Virus Serotype 2 Replication.

During infection with dengue viruses (DENVs), the lipid landscape within host cells is significantly altered to assemble membrane platforms that support viral replication and particle assembly. Fatty acyl-CoAs are key intermediates in the biosynthesis of complex lipids that form these membranes. They also function as key signaling lipids in the cell. Here, we carried out loss of function studies on acyl-CoA thioesterases (ACOTs), a family of enzymes that hydrolyze fatty acyl-CoAs to free fatty acids and coenzyme A, to understand their influence on the lifecycle of DENVs. The loss of function of the type I ACOTs 1 (cytoplasmic) and 2 (mitochondrial) together significantly increased DENV serotype 2 (DENV2) viral replication and infectious particle release. However, isolated knockdown of mitochondrial ACOT2 significantly decreased DENV2 protein translation, genome replication, and infectious virus release. Furthermore, loss of ACOT7 function, a mitochondrial type II ACOT, similarly suppressed DENV2. As ACOT1 and ACOT2 are splice variants, these data suggest that functional differences and substrate specificities due to the location (cytosol and mitochondria, respectively) of these proteins may account for the differences in DENV2 infection phenotype. Additionally, loss of mitochondrial ACOT2 and ACOT7 expression also altered the expression of several ACOTs located in multiple organelle compartments within the cell, highlighting a complex relationship between ACOTs in the DENV2 virus lifecycle.

Mometasone absorption in cultured airway epithelium.

BACKGROUND: Topical mometasone is frequently used as an intranasal spray, on drug-eluting stents, and compounded by specialty pharmacies as a sinus rinse. A typical sinus rinse contains 1.2 mg of mometasone dissolved in 240 mL of buffered saline and is flushed through the sinonasal cavity. The mometasone irrigation rapidly flows to the contralateral sinonasal cavity or the nasopharynx with a contact time on the order of 5 to 10 seconds. However, no information is available on the absorption rate of topical mometasone on the sinonasal surface. METHODS: To determine the absorption characteristics of mometasone, we harvested nasal epithelium from 2 healthy donors and differentiated them into a mature ciliated epithelium on Millicell membranes. We applied mometasone to the apical surface for various time intervals and then rinsed off non-absorbed mometasone with phosphate-buffered saline. Millicell membranes with the adherent epithelial cells were then harvested and stored in guanidine hydrochloride for quantification using high-performance liquid chromatography-mass spectrometry. RESULTS: Fifty percent of the maximal absorption occurred after an average of 38 minutes after application, and maximal absorption occurred after an average of 114 minutes. CONCLUSION: Our data provide an estimate for rates of absorption of mometasone applied to the sinonasal cavity and suggest that the absorption rates poorly match contact time during saline lavage.