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Effects of lifestyle intervention on soluble CD163, a macrophage activation marker, in patients with non-alcoholic fatty liver disease.
Rødgaard-Hansen, S, St George, A, Kazankov, K, Bauman, A, George, J, Grønbæk, H, Jon Møller, H
Scandinavian journal of clinical and laboratory investigation. 2017;(7):498-504
Abstract
OBJECTIVE Liver macrophages play an important role in the pathogenesis of non-alcoholic fatty liver disease (NAFLD). Soluble CD163 (sCD163), a macrophage-specific biomarker, reflects disease activity in the range of liver diseases. The impact of lifestyle intervention on sCD163 in adult NAFLD patients has not been investigated. MATERIAL AND METHODS We assessed 126 NAFLD patients participating in a lifestyle intervention study for sCD163 concentrations at baseline, after the three-month intervention period, and at long-term follow-up after 12 and 24 months. RESULTS The median sCD163 concentration at baseline was 2.59 mg/L (IQR = 1.78-3.63 mg/L). There was a significant decrease in sCD163 from baseline to three months follow-up (-0.64 mg/L, p < .001) with no difference between the four study groups (p = .6). At 12 and 24 months follow-up, the sCD163 concentrations had returned to baseline level (p = .3 and p = .1). Baseline sCD163 correlated with liver biomarkers and metabolic variables. There was a significantly greater decrease in sCD163 in patients who had a decrease in alanine aminotransferase (ALT) compared with patients with unchanged or increased ALT (-0.76 mg/L vs. -0.41 mg/L, p = .02), and in patients with a decrease in HOMA-IR compared with individuals with no decrease (-0.86 mg/L vs. -0.55 mg/L, p = .03). CONCLUSION sCD163 is associated with markers of liver necro-inflammation and glucose homoeostasis in NAFLD. Participation in a lifestyle intervention programme resulted in a significant reduction in sCD163. Our data support the utility of sCD163 as a biomarker for monitoring the efficacy of therapeutic interventions in NAFLD.
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Reduction of soluble CD163, substance P, programmed death 1 and inflammatory markers: phase 1B trial of aprepitant in HIV-1-infected adults.
Tebas, P, Spitsin, S, Barrett, JS, Tuluc, F, Elci, O, Korelitz, JJ, Wagner, W, Winters, A, Kim, D, Catalano, R, et al
AIDS (London, England). 2015;(8):931-9
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OBJECTIVE We evaluated safety, antiviral, immunomodulatory and anti-inflammatory properties of aprepitant - a neurokinin 1 receptor antagonist. DESIGN Phase IB randomized, placebo-controlled, double-blinded study. METHODS Eighteen patients were randomized (nine to aprepitant and nine to placebo). The patients received once-daily treatment (375 mg aprepitant or placebo by oral administration) for 2 weeks and were followed off drug for 4 weeks. RESULTS There were no significant changes in the plasma viremia or CD4(+) T cells during the dosing period. Aprepitant treatment was associated with significant decreases of median within patient change in percentages of CD4(+) T cells expressing programmed death 1 (-4.8%; P = 0.04), plasma substance P (-34.0 pg/ml; P = 0.05) and soluble CD163 (-563 ng/ml; P = 0.02), with no significant changes in the placebo arm. Mean peak aprepitant plasma concentration on day 14 was 7.6 ± 3.1 μg/ml. The use of aprepitant was associated with moderate increases in total cholesterol, low-density lipoprotein and high-density lipoprotein (median change = +31 mg/dl, P = 0.01; +26 mg/dl, P = 0.02; +3 mg/dl, P = 0.02, respectively). CONCLUSION Aprepitant was safe and well tolerated. At the dose used in this proof-of-concept phase IB study, aprepitant did not show a significant antiviral activity. Aprepitant-treated patients had decreased numbers of CD4(+) programmed death 1-positive cells and decreased plasma levels of substance P and soluble CD163, suggesting that blockade of the neurokinin 1 receptor pathway has a role in modulating monocyte activation in HIV infection. Prospective studies in virologically-suppressed individuals are warranted to evaluate the immunomodulatory properties of aprepitant. Exposures exceeding those attained in this trial are more likely to elicit clinical benefit.
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Elevated serum soluble CD200 and CD200R as surrogate markers of bone loss under bed rest conditions.
Kos, O, Hughson, RL, Hart, DA, Clément, G, Frings-Meuthen, P, Linnarsson, D, Paloski, WH, Rittweger, J, Wuyts, F, Zange, J, et al
Bone. 2014;:33-40
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CD200 is a transmembrane protein that belongs to the immunoglobulin family of proteins and is ubiquitously expressed on a variety of cell types. Upon interaction with its receptors (CD200Rs) expressed on myeloid-derived cells and T lymphocytes, an immunoregulatory signal is delivered to receptor-expressing cells. Previous studies have implicated a role for CD200:CD200R in the regulation of the expression of mRNA markers of osteoclastogenesis/osteoblastogenesis, following interaction of CD200 (on osteoblast precursors) with CD200R1 (on osteoclast precursors). Signaling of CD200R1 is hypothesized to attenuate osteoclastogenesis. We have investigated whether levels of soluble forms of CD200 and/or CD200R1 (sCD200, sCD200R1) are altered in volunteers undergoing 6° head down tilt bed rest to mimic conditions of microgravity known to be associated with preferential osteoclastogenesis and whether countermeasures, reported to be beneficial in attenuation of bone loss under microgravity conditions, would lead to altered sCD200 and sCD200R1 levels. Our data suggest that, as predicted, sCD200 levels fall under bed rest conditions while sCD200R1 levels rise. In subjects undergoing 30-minute per day continuous centrifugation protocols, as a countermeasure to attenuate changes which may lead to bone loss, these alterations in sCD200 and sCD200R1 levels seen under conditions of bed rest were abolished or attenuated. Our results suggest that measurement of sCD200 and/or sCD200R1 may prove a useful and rapid means of monitoring subjects at risk of bone loss and/or accessing the efficacy of treatment regimes designed to counter bone loss.
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Repeated supra-maximal sprint cycling with and without sodium bicarbonate supplementation induces endothelial microparticle release.
Kirk, RJ, Peart, DJ, Madden, LA, Vince, RV
European journal of sport science. 2014;(4):345-52
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Under normal homeostatic conditions, the endothelium releases microparticles (MPs), which are known to increase under stressful conditions and in disease states. CD105 (endoglin) and CD106 (vascular cell adhesion molecule-1) are expressed on the surface of endothelial cells and increased expression in response to stress may be observed. A randomised-controlled double-blinded study aimed to examine the use of endothelial MPs as a marker for the state of one's endothelium, as well as whether maintaining acid-base homeostasis affects the release of these MPs. This study tested seven healthy male volunteers, who completed a strenuous cycling protocol, with venous blood analysed for CD105+ and CD106+ MPs by flow cytometry at regular intervals. Prior to each trial participants consumed either 0.3 g·kg(-1) body mass of sodium bicarbonate (NaHCO3), or 0.045 g·kg(-1) body mass of sodium chloride (NaCl). A significant rise in endothelial CD105+ MPs and CD106+ MPs (p<0.05) was observed at 90 min post-exercise. A significant trend was shown for these MPs to return to resting levels 180 min post-exercise in both groups. No significance was found between experimental groups, suggesting that maintaining acid-base variables closer to basal levels has little effect upon the endothelial stress response for this particular exercise mode. In conclusion, strenuous exercise is accompanied by MP release and the endothelium is able to rapidly recover in healthy individuals, whilst maintaining acid-base homeostasis does not attenuate the MP release from the endothelium after exercise.
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Expression of the macrophage antigen CD163 in rectal cancer cells is associated with early local recurrence and reduced survival time.
Shabo, I, Olsson, H, Sun, XF, Svanvik, J
International journal of cancer. 2009;(8):1826-31
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Expression of the macrophage antigen CD163 in breast cancer cells is recently shown to be related to early distant recurrence and shortened survival. In this study, 163 patients with rectal cancer, included in the Swedish rectal cancer trial and followed up for a median of 71 months, were examined for the expression of CD163 in the primary tumors. The cancer cells expressed CD163 in the primary tumors in 23% (n = 32) of the patients. In pretreatment biopsies from 101 patients, 10 had CD163-positive cancers and these patients had earlier local recurrence (p < 0.044) and reduced survival time (p < 0.045) compared with those with CD163-negative tumors. When studying surgical specimens from 61 patients randomized to preoperative irradiation (5 x 5 Gy delivered in 1 week), it was found that 31% were CD163 positive whereas the corresponding figure was only 17% for 78 patients who were nonirradiated (p < 0.044), which tentatively may be consistent with X-rays inducing fusion. In CD163-positive tumors there was a reduced apoptotic activity as measured with the Termina deoxynucleotidyl Transferase Biotin-dUTP Nick End Labeling (TUNEL) technique (p = 0.018). There tended also to be an increased proliferation activity measured as an expression of Ki-67 non significant (NS). It is concluded that primary rectal cancers may express CD-163, and this phenotypic macrophage trait is related to early local recurrence, shorter survival time and reduced apoptosis. Furthermore, the expression of CD163 is more common after irradiation.
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Unmetabolized folic acid and total folate concentrations in breast milk are unaffected by low-dose folate supplements.
Houghton, LA, Yang, J, O'Connor, DL
The American journal of clinical nutrition. 2009;(1):216-20
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BACKGROUND Many lactating women in North America are exposed to high synthetic folic acid intakes because of food fortification and vitamin supplement use. Few data exist on the potential long-term effect of high folic acid intakes on milk folate concentrations, whereas no data are available on the effect of supplemental [6S]-5-methyltetrahydrofolate ([6S]-5-methylTHF). OBJECTIVE The aim of the present study was to investigate the effect of 3 treatments (placebo, folic acid, and [6S]-5-methylTHF) on milk folate and folate-binding protein (FBP) concentrations and to determine whether unmetabolized folic acid is present in milk. DESIGN In this 16-wk randomized, placebo-controlled intervention, 69 lactating women were randomly assigned to receive [6S]-5-methylTHF (416 microg/d, 906 nmol/d) or a placebo, or were assigned to receive folic acid (400 microg/d, 906 nmol/d) within 1 wk postpartum. Total milk folate, FBP, and unmetabolized folic acid concentrations were measured at 16 wk. RESULTS Unmetabolized folic acid was detected in 96% of milk samples tested representing approximately 8% of total milk folate concentrations. Total milk folate, FBP, and the proportion of unmetabolized milk folic acid did not differ between treatments; however, FBP concentrations were significantly lower than those published before mandatory folic acid fortification of the food supply. CONCLUSION Maternal intake of synthetic folic acid leads to the appearance of unmetabolized folic acid in milk and, seemingly, a down-regulation of milk FBP synthesis. The impact of these changes on the bioavailability of folate in infants requires further exploration.
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Enhanced adiponectin multimer ratio and skeletal muscle adiponectin receptor expression following exercise training and diet in older insulin-resistant adults.
O'Leary, VB, Jorett, AE, Marchetti, CM, Gonzalez, F, Phillips, SA, Ciaraldi, TP, Kirwan, JP
American journal of physiology. Endocrinology and metabolism. 2007;(1):E421-7
Abstract
Circulating adiponectin is reduced in disorders associated with insulin resistance. This study was conducted to determine whether an exercise/diet intervention would alter adiponectin multimer distribution and adiponectin receptor expression in skeletal muscle. Impaired glucose-tolerant older (>60 yr) obese (BMI 30-40 kg/m(2)) men (n = 7) and women (n = 14) were randomly assigned to 12 wk of supervised aerobic exercise combined with either a hypocaloric (ExHypo, approximately 500 kcal reduction, n = 11) or eucaloric diet (ExEu, n = 10). Insulin sensitivity was determined by the euglycemic (5.0 mM) hyperinsulinemic (40 mU x m(-2) x min(-1)) clamp. Adiponectin multimers [high (HMW), middle (MMW), and low molecular weight (LMW)] were measured by nondenaturing Western blot analysis. Relative quantification of adiponectin receptor expression through RT-PCR was determined from skeletal muscle biopsy samples. Greater weight loss occurred in ExHypo compared with ExEu subjects (8.0 +/- 0.6 vs. 3.2 +/- 0.6%, P < 0.0001). Insulin sensitivity improved postintervention in both groups (ExHypo: 2.5 +/- 0.3 vs. 4.4 +/- 0.5 mg x kg FFM(-1) x min(-1), and ExEu: 2.9 +/- 0.4 vs. 4.1 +/- 0.4 mg x kg FFM(-1) x min(-1), P < 0.0001). Comparison of multimer isoforms revealed a decreased percentage in MMW relative to HMW and LMW (P < 0.03). The adiponectin SA ratio (HMW/total) was increased following both interventions (P < 0.05) and correlated with the percent change in insulin sensitivity (P < 0.03). Postintervention adiponectin receptor mRNA expression was also significantly increased (AdipoR1 P < 0.03, AdipoR2 P < 0.02). These data suggest that part of the improvement in insulin sensitivity following exercise and diet may be due to changes in the adiponectin oligomeric distribution and enhanced membrane receptor expression.
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Genetic variation in leptin receptor gene is associated with type 2 diabetes and body weight: The Finnish Diabetes Prevention Study.
Salopuro, T, Pulkkinen, L, Lindström, J, Eriksson, JG, Valle, TT, Hämäläinen, H, Ilanne-Parikka, P, Keinänen-Kiukaanniemi, S, Tuomilehto, J, Laakso, M, et al
International journal of obesity (2005). 2005;(10):1245-51
Abstract
OBJECTIVE Genetic variation in leptin receptor (LEPR) gene has been reported to associate with insulin and glucose metabolism and adiposity in different study settings and various populations. We wanted to evaluate the association between LEPR polymorphisms, diabetes risk and body weight in Finnish subjects with impaired glucose tolerance (IGT). METHODS We investigated the associations of the three LEPR polymorphisms (Lys109Arg, Gln223Arg, 3'UTR Del/Ins) with the conversion to type 2 diabetes and the changes in body weight in 507 individuals with IGT participating in the Finnish Diabetes Prevention Study. Participants were randomized to either an intensive diet and exercise intervention group or a control group. RESULTS After 3 years, the odds ratio for the development of type 2 diabetes in individuals in the control group with the Lys109Lys genotype was 2.38-fold higher than in individuals with other genotype combinations (P=0.016). Irrespective of group individuals with the Gln223Gln genotype had higher conversion to type 2 diabetes (OR 2.01 (95% CI 1.03-3.93)) than the Arg223 allele carriers (P=0.042). The risk was more pronounced in the control group than in the intervention group. Individuals having the 3'UTR Del/Del genotype had a slightly higher body weight throughout the study than those with the insertion allele (P=0.020), although no difference in weight change was observed. CONCLUSION Two polymorphisms (Lys109Arg, Gln223Arg) in the extracellular domain of the leptin receptor predicted the conversion to type 2 diabetes in high-risk individuals with IGT. The Del/Ins polymorphism in the 3'UTR of LEPR was associated with body weight.
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Common leptin receptor polymorphisms do not modify the effect of alcohol ingestion on serum leptin levels in a controlled feeding and alcohol ingestion study.
Roth, MJ, Paltoo, DN, Albert, PS, Baer, DJ, Judd, JT, Tangrea, J, Taylor, PR
Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology. 2005;(6):1576-8
Abstract
We explored whether serum leptin response to alcohol ingestion was related to common leptin receptor gene polymorphisms, K109R (Lys109Arg), Q223R (Gln223Arg), S343S [Ser(T)343Ser(C)], and K656N (Lys656Asn), of reported physiologic significance during a controlled intervention. Fifty-three participants rotated through three 8-week treatment periods and consumed 0, 15 (equivalent to one drink), or 30 g (equivalent to two drinks) of alcohol (95% ethanol in 12 ounces of orange juice) per day, in random order. During the controlled feeding periods, all food and beverages including alcoholic beverages were prepared and supplied by the staff of the Beltsville Human Nutrition Research Center's Human Study Facility (Beltsville, MD), and energy intake was adjusted to maintain a constant weight. Blood was collected after an overnight fast on 3 separate days during the last week of each controlled feeding period and pooled for hormone analysis. Circulating serum leptin concentration was measured in duplicate by RIA and genotype analysis was done on DNA extracted from WBC using real-time PCR analysis amplification (TaqMan). Linear mixed models with a single random intercept reflecting a participant effect were used to estimate changes in serum leptin levels at 15 and 30 g of alcohol per day relative to 0 g of alcohol per day. No significant effects were found between common leptin receptor polymorphisms and serum leptin levels (P > or = 0.26).
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Calcium sensing receptor gene A986S polymorphism and responsiveness to calcium supplementation in postmenopausal women.
Young, R, Wu, F, Van de Water, N, Ames, R, Gamble, G, Reid, IR
The Journal of clinical endocrinology and metabolism. 2003;(2):697-700
Abstract
Recently several studies in adolescent girls or premenopausal women have implicated the calcium sensing receptor (CASR) gene A986S polymorphism in calcium and bone metabolism. However, the role of this genetic variant in postmenopausal women, specifically the development of osteoporosis, is unknown. This study reports the findings of a randomized, double-blind, placebo-controlled study of healthy postmenopausal women followed for 2 yr while taking placebo or supplementary calcium. Specifically, we examined the relationship between the CASR A986S polymorphism, bone biochemical profile, and bone mineral density at baseline and after 2 yr of treatment. We found no effect of this genetic variant in postmenopausal women at baseline or in response to calcium supplementation. These results are in contrast to those in young or premenopausal women, and they provide no support for an important role for the CASR A986S polymorphism in osteoporosis.