Genetic Effects on Postprandial Variations of Inflammatory Markers in Healthy Individuals

Circulating levels of inflammatory markers predict the risk of cardiovascular disease (CVD), mediated perhaps in part by dietary fat intake, through mechanisms only partially understood. To evaluate post‐fat load changes in inflammatory markers and genetic influences on these changes, we administered a standardized high‐fat meal to 838 related Amish subjects as part of the Heredity and Phenotype Intervention (HAPI) Heart Study and measured a panel of inflammatory markers, including C‐reactive protein (CRP), interleukin‐1β (IL‐1β), matrix metalloproteinase‐1 and ‐9 (MMP‐1 and MMP‐9), and white blood cell (WBC) count, before and 4 h after fat challenge (CRP prechallenge only). Heritabilities (h² ± s.d.) of basal inflammatory levels ranged from 16 ± 8% for MMP‐9 (P = 0.02) to 90 ± 7% for MMP‐1 (P < 0.0001). Post‐fat load, circulating levels of WBC, MMP‐1, and MMP‐9 increased by 16, 32, and 43% (all P < 0.0001), with no significant changes in IL‐1β. Postprandial changes over the 4‐h period were modestly heritable for WBC (age‐ and sex‐adjusted h² = 14 ± 9%, P = 0.04), but the larger MMP‐1 and MMP‐9 changes appeared to be independent of additive genetic effects. These results reveal that a high‐fat meal induces a considerable inflammatory response. Genetic factors appear to play a significant role influencing basal inflammatory levels but to have minimal influence on post‐fat intake inflammatory changes.     

Negative Association between Testosterone Concentration and Inflammatory Markers in Young Men: A Nested Cross-Sectional Study

Objective

Low grade systemic inflammation (LGSI) as well as androgen deficiency has in older men been associated with several pathologies, including cardiovascular disease (CVD). We wanted to investigate whether low testosterone levels are linked to biomarkers of LGSI already in young age, before any concurrent manifestations of CVD or other systemic diseases.

Design

Nested cross-sectional study.

Methods

Forty subfertile biochemically hypogonadal (n = 20) or eugonadal (n = 20) men (mean age 37 years, SD = 4.3) and 20 age-matched controls were randomly selected from an ongoing study on male subfertility. Subjects comprised male partners in infertile couples in whom also subnormal sperm concentration was present. Blood sampling, interviews, and anthropometric measures were undertaken. Serum levels of testosterone, LH, estradiol, SHBG, and 21 LGSI-markers were assessed.

Results

Among 21 inflammatory markers, macrophage inflammatory protein 1-alpha (MIP1a) (ß = −0.025; p = 0.028), 1-beta (MIP1B) (ß = −0.015; p = 0.049) and tumor necrosis factor alpha (TNFa) (ß = −0.015; p = 0.040) showed negative association to total testosterone (TT) levels. MIP1a (ß = −1.95; p = 0.001) and TNFa (ß = −0.95; p = 0.014) showed negative association to calculated free testosterone (cFT) levels. Compared to men with normal TT and cFT levels, TNFa levels were higher in men with subnormal levels of TT (mean ratio 1.61; p = 0.006) and cFT (mean ratio 1.58; p = 0.007). Also, MIP1a levels were higher in men with subnormal levels of TT (mean ratio 1.84; p = 0.030).

Conclusions

Subnormal testosterone may already in young age associate to LGSI, which might be a part of the mechanism underlying adverse health outcomes of male hypogonadism.     

Serum Levels of Inflammatory Markers in Depressed Elderly Patients with Diabetes and Mild Cognitive Impairment

Objective

The aim of the study was to determine the serum levels of CRP, IL-6 and TNF-α in elderly diabetic patients with depressive syndrome alone or with coexisting mild cognitive impairment (MCI).

Methods

276 diabetics elders were screened for depressive symptoms (using Geriatric Depression Scale: GDS-30) and MCI (using the Montreal Cognitive Assessment: MoCA score). Data of HbA1c, blood lipids and inflammatory markers levels were collected.

Results

In all groups of patients levels of CRP, IL-6 and TNF-α were significantly higher as compared to controls. The highest level of inflammatory markers was detected in group with depressive mood and coexisting MCI, however IL-6 level didn’t significantly differ as compared to MCI group. We founded correlations between all inflammatory markers in group of patients with depressive mood and in group of subjects with depressive symptoms and coexisting MCI. GDS-30 score was correlated with levels of inflammatory markers in group with depressive mood, and with levels of CRP and TNF-α in group with depressive mood and coexisting MCI. In the group with depressive mood and coexisting MCI we founded that MoCA score was negatively correlated with CRP and TNF-α levels; and HbA1c level was positively correlated with all inflammatory markers. The univariate logistic regression models revealed that variables which increased the likelihood of having been diagnosed with MCI in depressed patients were: higher levels of HbA1c, CRP, IL-6 and TNF-α, previous CVD or stroke, increased number of co-morbidities and microvascular complications, older age, less years of formal education. The multivariable model showed that previous CVD, higher HbA1c and IL-6 levels are significant factors.

Conclusions

We demonstrated that the presence of depressive syndrome is associated with higher levels of inflammatory markers in elderly patients with diabetes. The presence of MCI in these depressed subjects has additive effect on levels of inflammatory mediators.     

Changes in Electrocardiographic Parameters in Males of the European North as Markers of Climate- and Age-Related Effects

Electrocardiographic (ECG) amplitude- and time-related characteristics were determined in 20- to 59-year-old healthy male residents of the European north (the zone from 60° to 70° N). They were found to display increased amplitudes of some ECG waves, as well as prolonged P waves and R–R intervals, as compared to residents of warmer regions. In men, with age, the electrical axis of the heart shifts leftward and the heart tends to rotate counterclockwise about its longitudinal axis. Increased amplitudes of the P and S waves, as well as decreased amplitudes of theQ, R, and T waves, a lower position of the ST segment relative to the isoelectric line, and a prolongation of the P wave; the P–Q, Q–T, and R–R intervals; and the ST segment were observed in most of the leads. A regional variant of the age-specific amplitude- and time-related characteristics of the ECG is suggested for healthy male residents of the north.     

炎症标记物与缺血性中风预后评价

缺血性中风触发的炎症反应是一个级联放大过程,不仅可直接对缺血脑组织造成继发性损伤,还可通过与其他病理生理通路的相互影响、相互促进,共同对缺血后脑组织造成不可逆损伤。因此,采用炎症标记物对脑缺血损伤及其预后进行评价,具有重要临床意义。临床研究发现,多炎症标记物法用于缺血性中风的诊治和预后评价比单炎症标记物法更全面、更准确,故更具明显优势。综述脑缺血引发的炎症机制、脑缺血所致炎症通路与其他病理生理通路( 如氧化应激、细胞凋亡和兴奋性毒性) 的关联以及炎症标记物在缺血性中风预后评价中的应用。     

The Chronic Effects of Whey Proteins on Blood Pressure,Vascular Function,and Inflammatory Markers in Overweight Individuals

Limited evidence suggests that dairy whey protein may be the major dairy component that is responsible for health benefits currently associated with increased dairy consumption. Whey proteins may reduce blood pressure and improve cardiovascular health. This study evaluated the effects of whey protein supplementation on blood pressure, vascular function and inflammatory markers compared to casein and glucose (control) supplementation in overweight/obese individuals. The subjects were randomized to either whey protein, casein or glucose supplementation for 12 weeks according to a parallel design. In all, 70 men and women with a mean (±s.e.m.) BMI (kg/m²) of 31.3 ± 0.8 completed the study. Systolic blood pressure (SBP) decreased significantly at week 6 compared to baseline in the whey and casein groups, (P = 0.028 and P = 0.020, respectively) and at week 12 (P = 0.020, and P = 0.017, respectively). Diastolic blood pressure (DBP) decreased significantly compared to baseline in the whey and casein groups (P = 0.038 and P = 0.042, respectively) at week 12. DBP decreased significantly in the whey and casein groups (P = 0.025, P = 0.038, respectively) at week 12 compared to the control group. Augmentation index (AI) was significantly lower from baseline at 12 weeks (P = 0.021) in the whey group. AI decreased significantly in the whey group at 12 weeks compared to control (P = 0.006) and casein (P = 0.006). There were no significant changes in inflammatory markers within or between groups. This study demonstrated that supplementation with whey protein improves blood pressure and vascular function in overweight and obese individuals.     

Effects of Endurance Exercise on Nocturnal Hormone Concentrations in Males

A preliminary study was conducted to evaluate the change in nocturnal concentrations of testosterone, luteinizing hormone, growth hormone, prolactin, thyroxine, and Cortisol following a control day (no exercise) and on a day in which exercise was performed. Exercise consisted of 90 min of cycling at 70% of each subject's maximal oxygen uptake. The exercise occurred from 1630 to 1800 hr on the exercise day while a comparable period of rest took place on the control day. Hormonal concentrations were evaluated at 2-hr intervals for a 12-hr period each night (2000-0800 hr). The subjects slept from 2255 (± 20 min [x ± S.E.M.]) until 0715 (± 15) during each night. All hormone responses were plotted and integrated for the 12-hr period. Analysis indicated that a significant augmentation of the prolactin and thyroxine responses occurred, while concurrently an attenuation of the growth hormone and Cortisol responses were observed. Contrastingly, no significant effects were found for the testosterone and luteinizing hormones responses. The physiological significance of these findings remained to be determined, but the results do suggest that further research is warranted in the area.     

Effects of Thiazolidinedione Therapy on Inflammatory Markers of Type 2 Diabetes: A Meta-Analysis of Randomized Controlled Trials

Background

Inflammation is a common feature in patients with type 2 diabetes mellitus (T₂DM). This meta-analysis aimed to assess the influence of thiazolidinedione (TZD) therapy on the circulating levels of inflammatory markers in patients with T₂DM.

Methods and Results

We searched the databases Medline, Embase, ScienceDirect, Web of Science, SpringerLink, and the Cochrane Library for randomized controlled trials (RCTs) that examined the effects of thiazolidinedione vs. a placebo on patients with T₂DM. The main outcomes were absolute changes in levels of circulating inflammatory markers. Twenty-seven RCTs were included and data were analyzed using a fixed-effect model or a random-effect model based on heterogeneity. Pooled results indicated that circulating levels of high-sensitivity C reactive protein (hsCRP; SMD = –0.65, 95% CI = –0.98 to –0.32, p < 0.01), monocyte chemoattractant protein-1 (MCP-1; WMD = –54.19, 95% CI = –73.86 to –34.52, p < 0.01), von Willebrand factor% (vWF%; WMD = –8.18, 95% CI = –13.54 to –2.81, p 0.01), fibrinogen (SMD = –0.26, 95% CI = –0.41 to –0.11, p < 0.01) and E-selectin(WMD = –3.57, 95% CI = –5.59 to -1.54, p <0.01) were significantly decreased after TZD therapy. However, interleukin-6 (IL-6), matrix metalloproteinase-9 (MMP-9), soluble CD40 ligand, plasminogen activator inhibitor 1 (PAI-1) and intercellular adhesion molecule (ICAM-1) were not significantly affected. Subgroup analyses of PAI-1, vWF% and fibrinogen in terms of trial drugs showed significant reductions for rosiglitazone (all p valuses< 0.05), but not pioglitazone treatment. Conversely, the E-selectin (p < 0.01) lowering effect only existed in the pioglitazone group. Further, rosiglitazone and pioglitazone treatment reduced serum hsCRP and MCP-1 but had no marked effects on MMP-9, IL-6 and ICAM-1.

Conclusions

Limited evidence suggested that TZD therapy had anti-inflammatory property that might contribute to its beneficial effect on inflammatory state in patients with type 2 diabetes.     

Effect of Zinc Supplementation on Inflammatory Markers and Adipokines in Young Obese Women

Obesity is a chronic inflammatory state characterized by altered adipokine production and increased levels of inflammatory cytokines. The study explored the effect of zinc supplementation on inflammatory markers and adipocyte hormones in young obese women. Twenty five non-obese women and forty obese women (body mass index ≥25 kg/m²) aged 19–28 years were recruited for this study. Twenty obese women of the study group took 30 mg/day of supplemental zinc as zinc gluconate for 8 weeks and 20 obese women of control group took placebo. Usual dietary zinc intake was estimated from 3-day diet records. Serum zinc and urinary zinc concentration were measured by Atomic Absorption Spectrophotometry. Inflammatory markers such as high sensitivity C-reactive protein (hs-CRP), tumor necrosis factor-alpha (TNF-α), and interleukin (IL)-6 and adipocyte hormones such as lepin and adiponectin were measured by enzyme immunoassay. Inflammatory markers and leptin were significantly higher, but adiponectin was significantly lower in obese women than non-obese women. Zinc supplementation increased serum zinc by 15 % and urinary zinc by 56 % (P?<?0.05). The levels of hs-CRP (P?=?0.03) and IL-6 (P?=?0.006) significantly decreased with zinc supplementation, but not in placebo group. Serum leptin and plasma adiponectin concentration did not differ with either zinc supplementation or placebo. The levels of IL-6 and leptin were inversely associated with dietary zinc intake. These results suggest that zinc may have a favorable effect on obesity-related inflammation in young adults.     

Attenuated Age-Impact on Systemic Inflammatory Markers in the Presence of a Metabolic Burden

BackgroundThe overall burden of chronic disease, inflammation and cardiovascular risk increases with age. Whether the relationship between age and inflammation is impacted by presence of an adverse metabolic burden is not known.MethodsWe determined inflammatory markers in humans (336 Caucasians and 224 African Americans) and in mice, representing a spectrum of age, weight and metabolic burden.ResultsIn humans, levels of inflammatory markers increased significantly with age in subjects without the metabolic syndrome, (P=0.009 and P=0.037 for C-reactive protein, P<0.001 and P=0.001 for fibrinogen, P<0.001 and P=0.005 for serum amyloid-A, for Caucasians and African Americans, respectively). In contrast, trend patterns of inflammatory markers did not change significantly with age in subjects with metabolic syndrome in either ethnic group, except for fibrinogen in Caucasians. A composite z-score for systemic inflammation increased significantly with age in subjects without metabolic syndrome (P=0.004 and P<0.006 for Caucasians and African Americans, respectively) but not in subjects with metabolic syndrome (P=0.009 for difference in age trend between metabolic syndrome and non-metabolic syndrome). In contrast, no similar age trend was found in vascular inflammation. The findings in humans were paralleled by results in mice as serum amyloid-A levels increased across age (range 2-15 months, P<0.01) and were higher in ob/ob mice compared to control mice (P<0.001).ConclusionsPresence of a metabolic challenge in mice and humans influences levels of inflammatory markers over a wide age range. Our results underscore that already at a young age, presence of a metabolic burden enhances inflammation to a level that appears to be similar to that of decades older people without metabolic syndrome.     

Testosterone,Immune Function,and Life History Transitions in Filipino Males (Homo sapiens)

Testosterone contributes to male life history trade-offs through effects on behavior and energy usage. Testosterone’s role as a trade-off mediator is often discussed as manifesting partly through a negative impact on investment in survival, via immune suppression. Studies across species also show that testosterone in males commonly fluctuates with social changes, providing natural experiments to evaluate any potential immune impacts of intraindividual changes in testosterone. Using longitudinal data from Metropolitan Cebu City, the Philippines, we recently showed that men transitioning to fatherhood experienced substantial declines in testosterone over a 4.5-yr period. Drawing on a subsample of the same men here (N?=?330), we evaluate whether these socially mediated changes in testosterone are paralleled by changes in immune function as reflected in salivary secretory immunoglobulin A (SIgA), a localized marker of mucosal immunity. Men reporting more cold/flu symptoms had lower testosterone and a trend toward lower SIgA in cross-section. Intraindividual changes in testosterone between baseline and follow-up 4.5 yr later were strong, positive predictors of changes in SIgA. Men becoming new fathers did not differ in ΔSIgA compared to other men. The positive relationship between ΔSIgA and ΔT in this sample runs counter to the expectation of a mating–maintenance trade-off, and may reflect direct effects of androgens on SIgA production. Our results add to the dialogue on the complex relationships between the reproductive and immune axes, providing additional evidence that in humans testosterone is not uniformly immunosuppressive.     

Effects of Nandrolone Stimulation on Testosterone Biosynthesis in Leydig Cells

Anabolic androgenic steroids (AAS) are among the drugs most used by athletes for improving physical performance, as well as for aesthetic purposes. A number of papers have showed the side effects of AAS in different organs and tissues. For example, AAS are known to suppress gonadotropin‐releasing hormone, luteinizing hormone, and follicle‐stimulating hormone. This study investigates the effects of nandrolone on testosterone biosynthesis in Leydig cells using various methods, including mass spectrometry, western blotting, confocal microscopy and quantitative real‐time PCR. The results obtained show that testosterone levels increase at a 3.9 μM concentration of nandrolone and return to the basal level a 15.6 μM dose of nandrolone. Nandrolone‐induced testosterone increment was associated with upregulation of the steroidogenic acute regulatory protein (StAR) and downregulation of 17a‐hydroxylase/17, 20 lyase (CYP17A1). Instead, a 15.6 µM dose of nandrolone induced a down‐regulation of CYP17A1. Further in vivo studies based on these data are needed to better understand the relationship between disturbed testosterone homeostasis and reproductive system impairment in male subjects. J. Cell. Physiol. 231: 1385–1391, 2016. © 2015 The Authors. Journal of Cellular Physiology Published by Wiley Periodicals, Inc.     

Assessment of Predictive Markers for Placental Inflammatory Response in Preterm Births

Placental inflammatory response (PIR) is associated with adverse neonatal outcomes such as sepsis, cerebral palsy, low birth weight, preterm birth, and neonatal mortality. However, there is an urgent need for noninvasive and sensitive biomarkers for prediction of PIR. In this study, we evaluated the clinical usefulness of maternal serum inflammatory markers for prediction of PIR in women with impending preterm birth. We conducted a retrospective cohort study of 483 patients who delivered preterm neonates. Serum levels of leukocyte differential counts, C-reactive protein (CRP), and neutrophil to lymphocyte ratio (NLR) were compared between women with no placental inflammation and women with PIR. The mean neutrophil counts, CRP levels, and NLR in both the patients with histologic chorioamnionitis (HCA) alone and those with HCA with funisitis were significantly higher than those in women with no placental inflammation. Compared to leukocyte subset or CRP, NLR in women with funisitis was significantly higher than in women with HCA alone and showed higher predictive accuracy, along with 71.4% sensitivity, 77.9% specificity, 80.7% positive predictive value, and 67.8% negative predictive value for prediction of PIR. On Kaplan-Meier survival analysis, women with both an elevated level of CRP and a high NLR had a shorter admission-to-delivery interval compared to women with either an elevated level of CRP or a high NLR alone. NLR may be a predictive marker of PIR and could be used as a cost-effective parameter for identifying women at risk of PIR.     

Chronic Hyperhomocysteinemia Increases Inflammatory Markers in Hippocampus and Serum of Rats

This study investigated the effects of chronic homocysteine administration on some parameters of inflammation, such as cytokines (TNF-α, IL-1β and IL-6), chemokine CCL(2) (MCP-1), nitrite and prostaglandin E(2) levels, as well as on immunocontent of NF-κB/p65 subunit in hippocampus and/or serum of rats. Since acetylcholinesterase has been associated with inflammation, we also evaluated the effect of homocysteine on this enzyme activity in hippocampus of rats. Wistar rats received daily subcutaneous injections of homocysteine (0.3-0.6 μmol/g body weight) or saline (control) from the 6th to the 28th days-of-age. One or 12 h after the last injection, rats were euthanized and hippocampus and serum were used. Results showed that chronic hyperhomocysteinemia significantly increased pro-inflammatory cytokines (TNF-α, IL-1β and IL-6), chemokine CCL(2) (MCP-1) and prostaglandin E(2) in hippocampus and serum of rats at 1 and 12 h after the last injection of homocysteine. Nitrite levels increased in hippocampus, but decreased in serum at 1 h after chronic hyperhomocysteinemia. Acetylcholinesterase activity and immunocontent of citoplasmic and nuclear NF-κB/p65 subunit were increased in hippocampus of rats subjected to hyperhomocysteinemia at 1 h, but did not alter at 12 h after the last injection of homocysteine. According to our results, chronic hyperhomocysteinemia increases inflammatory parameters, suggesting that this process might be associated, at least in part, with the cerebrovascular and vascular dysfunctions characteristic of some homocystinuric patients.     

Testosterone Levels Are Negatively Associated with Childlessness in Males,but Positively Related to Offspring Count in Fathers

Variation in testosterone (T) is thought to affect the allocation of effort between reproductive and parenting strategies. Here, using a large sample of elderly American men (n = 754) and women (n = 669) we examined the relationship between T and self-reported parenthood, as well as the relationship between T and number of reported children. Results supported previous findings from the literature, showing that fathers had lower T levels than men who report no children. Furthermore, we found that among fathers T levels were positively associated with the number of children a man reports close to the end of his lifespan. Results were maintained when controlling for a number of relevant factors such as time of T sampling, participant age, educational attainment, BMI, marital status and reported number of sex partners. In contrast, T was not associated with either motherhood or the number of children women had, suggesting that, at least in this sample, T does not influence the allocation of effort between reproductive and parenting strategies among women. Findings from this study contribute to the growing body of literature suggesting that, among men, pair bonding and paternal care are associated with lower T levels, while searching and acquiring sex partners is associated with higher T levels.     

Serum Inflammatory Mediators as Markers of Human Lyme Disease Activity

Chemokines and cytokines are key signaling molecules that orchestrate the trafficking of immune cells, direct them to sites of tissue injury and inflammation and modulate their states of activation and effector cell function. We have measured, using a multiplex-based approach, the levels of 58 immune mediators and 7 acute phase markers in sera derived from of a cohort of patients diagnosed with acute Lyme disease and matched controls. This analysis identified a cytokine signature associated with the early stages of infection and allowed us to identify two subsets (mediator-high and mediator-low) of acute Lyme patients with distinct cytokine signatures that also differed significantly (p<0.0005) in symptom presentation. In particular, the T cell chemokines CXCL9 (MIG), CXCL10 (IP-10) and CCL19 (MIP3B) were coordinately increased in the mediator-high group and levels of these chemokines could be associated with seroconversion status and elevated liver function tests (p = 0.027 and p = 0.021 respectively). There was also upregulation of acute phase proteins including CRP and serum amyloid A. Consistent with the role of CXCL9/CXCL10 in attracting immune cells to the site of infection, CXCR3+ CD4 T cells are reduced in the blood of early acute Lyme disease (p = 0.01) and the decrease correlates with chemokine levels (p = 0.0375). The levels of CXCL9/10 did not relate to the size or number of skin lesions but elevated levels of serum CXCL9/CXCL10 were associated with elevated liver enzymes levels. Collectively these results indicate that the levels of serum chemokines and the levels of expression of their respective chemokine receptors on T cell subsets may prove to be informative biomarkers for Lyme disease and related to specific disease manifestations.     

The Inflammatory Potential of Dietary Manganese in a Cohort of Elderly Men

In the current study, 48 male rats were classified into four groups (12 rats/group): 1—control group received 1 ml distilled water, 2—origanum oil group treated daily with oral dose of origanum oil (5 mg/kg) for 30 and 60 days, 3—mercuric chloride group treated daily with oral dose of mercuric chloride (4 mg/kg) for 30 and 60 days, and 4—origanum oil + mercuric chloride group treated with both origanum oil and mercuric chloride (5 and 4 mg/kg, respectively) for 30 and 60 days. All treatments were carried out by stomach tube. The results showed that administration of mercuric chloride induced significant increase in thiobarbituric acid reactive substance (TBARS) and decrease in glutathione (GSH), catalase (CAT), and super oxide dismutase (SOD) in testis and spleen tissues. The data also showed significant increase in tumor necrossis factor-α (TNF-α), 8-hydroxy deoxyguanosine (8-OHDG), acid phosphatase (ACP), urea, and creatinine. Furthermore, significant decreases in serum zinc (Zn), copper (Cu), magnesium (Mg), iron (Fe), and testosterone in mercuric chloride group were recorded. The histological examination of testis and spleen tissues showed some degenerative changes while significant improvement in the antioxidant levels, biochemical, trace elements, and histological changes were observed in mercuric chloride group treated with origanum oil. It could be concluded that origanum oil through its antioxidant potential may possess health promoting properties and could protect cells from oxidative damage induced by mercuric chloride.