The effect of dietary supplementation with n-3 polyunsaturated fatty acids on the synthesis of interleukin-1 and tumor necrosis factor by mononuclear cells

We examined whether the synthesis of interleukin-1 or tumor necrosis factor, two cytokines with potent inflammatory activities, is influenced by dietary supplementation with n-3 fatty acids. Nine healthy volunteers added 18 g of fish-oil concentrate per day to their normal Western diet for six weeks. We used a radioimmunoassay to measure interleukin-1 (IL-1 beta and IL-1 alpha) and tumor necrosis factor produced in vitro by stimulated peripheral-blood mononuclear cells. With endotoxin as a stimulus, the synthesis of IL-1 beta was suppressed from 7.4 +/- 0.9 ng per milliliter at base line to 4.2 +/- 0.5 ng per milliliter after six weeks of supplementation (43 percent decrease; P = 0.048). Ten weeks after the end of n-3 supplementation, we observed a further decrease to 2.9 +/- 0.5 ng per milliliter (61 percent decrease; P = 0.005). The production of IL-1 alpha and tumor necrosis factor responded in a similar manner. Twenty weeks after the end of supplementation, the production of IL-1 beta, IL-1 alpha, and tumor necrosis factor had returned to the presupplement level. The decreased production of interleukin-1 and tumor necrosis factor was accompanied by a decreased ratio of arachidonic acid to eicosapentaenoic acid in the membrane phospholipids of mononuclear cells. We conclude that the synthesis of IL-1 beta, IL-1 alpha, and tumor necrosis factor can be suppressed by dietary supplementation with long-chain n-3 fatty acids. The reported antiinflammatory effect of these n-3 fatty acids may be mediated in part by their inhibitory effect on the production of interleukin-1 and tumor necrosis factor.     

In vitro production of IL 1 beta, IL 1 alpha, TNF and IL2 in healthy subjects: distribution, effect of cyclooxygenase inhibition and evidence of independent gene regulation

Numerous studies have reported altered in vitro cytokine production in various diseases. In the present study we used specific immunoassays to quantitate production of interleukin 1 beta (IL 1 beta), IL 1 alpha, tumor necrosis factor (TNF) and IL 2 from human peripheral blood mononuclear cells (PBMC). The distribution of cell-associated and secreted cytokines was studied in PBMC of 21 individuals; in response to lipopolysaccharide (LPS) the proportion of cell-associated IL 1 beta ranged from 13% to 56%, for IL 1 alpha 29% to 98%, and for TNF 2% to 17%. In a larger cohort of 32 subjects, the total amount of immunoreactive cytokines produced in response to LPS or phytohemagglutinin was normally distributed within the study group. Mean production of IL 1 alpha in response to LPS was 10.1 ng/ml and exceeded production of IL 1 beta (5.6 ng/ml) and TNF (2.2 ng/ml). The distribution pattern was characterized by high intersubject variability extending over two orders of magnitude and the presence of high and low "producers". Production of IL 1 alpha and IL 1 beta correlated (R = 0.69). In contrast, production of IL 1 beta did not correlate with production of TNF or IL 2. Indomethacin present during stimulation of PBMC increased the amount of IL 1 beta produced and showed a high correlation (R = 0.83) compared to cultures without indomethacin. Thus, low production of IL 1 beta in certain subjects appears not to be due to inhibitable levels of cyclooxygenase products. In a retrospective study, PBMC from 12 subjects who had taken oral cyclooxygenase inhibitors during the preceding 7 days produced 43% more IL 1 beta than subjects who did not take these drugs (p less than 0.05). These studies demonstrate that the amount of cytokine synthesized by PBMC (a) is regulated independently for IL 1, TNF and IL 2; (b) correlates for IL 1 beta and IL 1 alpha; (c) is intrinsic for low and high "producers", and (d) production of IL 1 beta increases with the use of oral cyclooxygenase inhibitors.     

Prevalence and correlates of chronic fatigue syndrome and post-traumatic stress disorder after the outbreak of the COVID-19

Journal of NeuroVirology - As the SARS-COV-2 becomes a global pandemic, many researchers have a concern about the long COVID-19 complications. Chronic fatigue syndrome/myalgic encephalomyelitis...     

Does prenylation predict progression in NAFLD?

Non-alcoholic fatty liver disease (NAFLD) often develops in concert with related metabolic diseases, such as obesity, dyslipidemia and insulin resistance. Prolonged lipid accumulation and inflammation can progress to non-alcoholic steatohepatitis (NASH). Although factors associated with the development of NAFLD are known, triggers for the progression of NAFLD to NASH are poorly understood. Recent findings published in The Journal of Pathology reveal the possible regulation of NASH progression by metabolites of the mevalonate pathway. Mevalonate can be converted into the isoprenoids farnesyldiphosphate (FPP) and geranylgeranyl diphosphate (GGPP). GGPP synthase (GGPPS), the enzyme that converts FPP to GGPP, is dysregulated in humans and mice during NASH. Both FPP and GGPP can be conjugated to proteins through prenylation, modifying protein function and localization. Deletion or knockdown of GGPPS favors FPP prenylation (farnesylation) and augments the function of liver kinase B1, an upstream kinase of AMP-activated protein kinase (AMPK). Despite increased AMPK activation, livers in Ggpps-deficient mice on a high-fat diet poorly oxidize lipids due to mitochondrial dysfunction. Although work from Liu et al provides evidence as to the potential importance of the prenylation portion of the mevalonate pathway during NAFLD, future studies are necessary to fully grasp any therapeutic or diagnostic potential. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

Significant Association of rs77493513 Polymorphism in 3'-UTR of the NRG1 Gene with the Risk of Multiple Sclerosis Disease

Metabolic Brain Disease - Multiple sclerosis (MS) is a chronic inflammatory and autoimmune disease characterized by demyelination of the central nervous system (CNS). Neuregulin 1 (NRG1) is a...     

Spoligotyping of Mycobacterium tuberculosis in anthracotic bronchitis

BACKGROUND: Mycobacterium tuberculosis infection has been shown to be associated with anthracotic bronchitis. However, the typical manifestation of infection is not usually present in infected patients, which raises the question of whether a particular strain of M. tuberculosis is associated with this group of patients. OBJECTIVE: To determine whether a particular strain of M. tuberculosis is associated with anthracotic bronchitis. DESIGN: We assessed the predominant space oligonucleotide (spoligotype) patterns of M. tuberculosis complex isolated from patients with anthracotic bronchitis and compared the results with tuberculosis (TB) subtype patterns in Iran and other countries. RESULTS: During a 7-month period (April--October 2006), we enrolled 87 patients (30 men and 57 women) with anthracotic bronchitis, 26% (n = 23) of whom had TB. Spoligotyping of M. tuberculosis among these 23 patients showed four distinct patterns: East-African-Indian (11, 47.8%) and Central-Asian (7, 30.4%), Haarlem I (4, 17.4%) and T-1 (1, 4.3%). When compared with spoligotype patterns of M. tuberculosis in Middle Eastern countries, including Iran, anthracotic bronchitis had similar patterns. CONCLUSION: Our results indicate that the atypical manifestations of TB in anthracotic patients are not caused by any particular subtypes of M. tuberculosis. We conclude that anthracotic bronchitis is actually an atypical presentation of tuberculous infection with common subtypes inside the bronchial mucosa.     

Distress tolerance and special alcohol metacognitions behave differently in the association of negative affect with alcohol-related patterns in men with problematic alcohol use in the abstinence phase

Negative affect may be related to alcohol-related patterns (e.g., craving and problematic alcohol use). Distress intolerance and positive and negative alcohol-related metacognitions may be underlying mechanisms in this link. This study aimed to evaluate the effect of negative affect including depressive, anxious, and stress symptoms on alcohol craving and problematic alcohol use via the paths of distress tolerance and both positive and negative alcohol-related metacognitions. Three hundred men with problematic alcohol use during the abstinence phase completed psychological and clinical measures. Results showed that craving and negative alcohol metacognitions mediated the relationship between negative affect and problematic alcohol use. Negative affect had a direct and positive effect on craving and indirect effect via distress intolerance and positive alcohol metacognitions. In turn, distress intolerance and positive alcohol metacognitions indirectly and positively affected problematic alcohol use via craving. The study indicates that distress tolerance and distinct alcohol metacognitions may be differently related to various patterns of alcohol-related problems, such that alcohol drinkers with high levels of negative affect, distress intolerance, and positive alcohol metacognitions show higher levels of craving, while high negative affect in relation to high negative alcohol metacognitions and alcohol craving is related to the perpetuation of alcohol use or problematic alcohol use.     

Metabolite Profiles During Oral Glucose Challenge

To identify distinct biological pathways of glucose metabolism, we conducted a systematic evaluation of biochemical changes after an oral glucose tolerance test (OGTT) in a community-based population. Metabolic profiling was performed on 377 nondiabetic Framingham Offspring cohort participants (mean age 57 years, 42% women, BMI 30 kg/m²) before and after OGTT. Changes in metabolite levels were evaluated with paired Student t tests, cluster-based analyses, and multivariable linear regression to examine differences associated with insulin resistance. Of 110 metabolites tested, 91 significantly changed with OGTT (P ≤ 0.0005 for all). Amino acids, β-hydroxybutyrate, and tricarboxylic acid cycle intermediates decreased after OGTT, and glycolysis products increased, consistent with physiological insulin actions. Other pathways affected by OGTT included decreases in serotonin derivatives, urea cycle metabolites, and B vitamins. We also observed an increase in conjugated, and a decrease in unconjugated, bile acids. Changes in β-hydroxybutyrate, isoleucine, lactate, and pyridoxate were blunted in those with insulin resistance. Our findings demonstrate changes in 91 metabolites representing distinct biological pathways that are perturbed in response to an OGTT. We also identify metabolite responses that distinguish individuals with and without insulin resistance. These findings suggest that unique metabolic phenotypes can be unmasked by OGTT in the prediabetic state.Diabetes affects >1 in 10 adults 20 years of age or older in the U.S., and more than one-third of all adults have prediabetes (1). Changes in traditional measures of glucose and insulin metabolism are known to occur years before the diagnosis of diabetes is made (2). Using high-throughput profiling of metabolic status, we have shown that elevations in plasma branched-chain and aromatic amino acids are also able to predict future diabetes in otherwise normoglycemic, healthy adults (3). Similarly, lipid profiling has demonstrated novel perturbations in triacylglycerol distribution that signal future diabetes risk (4). These findings highlight how emerging technologies are able to broaden our perspective on early disease states, potentially lending insights into biological mechanisms that underlie diabetes and metabolic disease. Characterizing early metabolic changes may also lead to the early identification of at-risk individuals and may prompt the initiation of proven preventive strategies (5).The oral glucose tolerance test (OGTT) provides a dynamic view of glucose and insulin physiology and has been widely used for decades to diagnose diabetes (6,7). Therefore, we conducted a systematic evaluation of biochemical changes after OGTT in a community-based population, with the goal of providing a broad view of the metabolic response to a glucose challenge. An important advantage of profiling plasma samples before and after glucose ingestion is that each individual is able to serve as their own biological control. In addition to attenuating noise attributable to interindividual variation, this approach limits confounding effects of diet, medications, and other inputs that impact the human metabolome. We used a liquid chromatography/mass spectrometry (LC/MS)–based platform that allowed highly specific identification of small molecules in a targeted manner. In prior pilot studies, our group has shown that metabolite excursions with OGTT revealed a switch from catabolism to anabolism, largely attributable to insulin actions (8). In the current study, we sought to evaluate perturbations with OGTT in an expanded panel of metabolites and in a more comprehensive population-based sample with a high propensity for the development of diabetes, and to investigate these changes in individuals with and without insulin resistance.     

A sleep schedule incorporating naps benefits the transformation of hierarchical knowledge

Study ObjectivesThe learning brain establishes schemas (knowledge structures) that benefit subsequent learning. We investigated how sleep and having a schema might benefit initial learning followed by rearranged and expanded memoranda. We concurrently examined the contributions of sleep spindles and slow-wave sleep to learning outcomes.MethodsFifty-three adolescents were randomly assigned to an 8 h Nap schedule (6.5 h nocturnal sleep with a 90-minute daytime nap) or an 8 h No-Nap, nocturnal-only sleep schedule. The study spanned 14 nights, simulating successive school weeks. We utilized a transitive inference task involving hierarchically ordered faces. Initial learning to set up the schema was followed by rearrangement of the hierarchy (accommodation) and hierarchy expansion (assimilation). The expanded sequence was restudied. Recall of hierarchical knowledge was tested after initial learning and at multiple points for all subsequent phases. As a control, both groups underwent a No-schema condition where the hierarchy was introduced and modified without opportunity to set up a schema. Electroencephalography accompanied the multiple sleep opportunities.ResultsThere were main effects of Nap schedule and Schema condition evidenced by superior recall of initial learning, reordered and expanded memoranda. Improved recall was consistently associated with higher fast spindle density but not slow-wave measures. This was true for both nocturnal sleep and daytime naps.ConclusionA sleep schedule incorporating regular nap opportunities compared to one that only had nocturnal sleep benefited building of robust and flexible schemas, facilitating recall of the subsequently rearranged and expanded structured knowledge. These benefits appear to be strongly associated with fast spindles.Clinical Trial registration{"type":"clinical-trial","attrs":{"text":"NCT04044885","term_id":"NCT04044885"}}NCT04044885 (https://clinicaltrials.gov/ct2/show/{"type":"clinical-trial","attrs":{"text":"NCT04044885","term_id":"NCT04044885"}}NCT04044885).