-
1.
Soluble CD163 correlates with lipid metabolic adaptations in type 1 diabetes patients during ketoacidosis.
Svart, M, Rittig, N, Møller, N, Møller, HJ, Gronbaek, H
Journal of diabetes investigation. 2019;(1):67-72
Abstract
INTRODUCTION Diabetic ketoacidosis (DKA) is associated with inflammation and increased lipolysis. The macrophage activation marker, soluble CD163 (sCD163), is associated with obesity, non-alcoholic fatty liver disease and type 2 diabetes. We aimed to investigate whether sCD163 correlates with key elements of lipolysis in type 1 diabetes patients during mild DKA. MATERIALS AND METHODS We investigated nine patients with type 1 diabetes twice during: (i) euglycemic control conditions and a bolus of saline; and (ii) hyperglycemic ketotic conditions induced by lipopolysaccharide administration combined with insulin deprivation. Blood samples, indirect calorimetry, palmitate tracer and adipose tissue biopsies were used to investigate lipid metabolism. RESULTS We observed a significant increase in plasma sCD163 levels after lipopolysaccharide exposure (P < 0.001). Concentrations of sCD163 were positively correlated with plasma concentrations of free fatty acids, palmitate rate of appearance and lipid oxidation rates, and negatively correlated to the expression of G0/G1 switch 2 gene messenger ribonucleic acid content in adipose tissue (P < 0.01 for all). Furthermore, sCD163 levels correlated positively with plasma peak concentrations of cortisol, glucagon, tumor necrosis factor-α, interleukin-6 and interleukin-10 (P < 0.01 for all). Data on lipolysis and inflammation have previously been published. CONCLUSIONS Macrophage activation assessed by sCD163 might play an important role in DKA, as it correlates strongly with important components of lipid metabolism including free fatty acids, palmitate, lipid oxidation, G0/G1 switch 2 gene and pro-inflammatory cytokines during initial steps of DKA. These results are novel and add important knowledge to the field of DKA.
-
2.
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
-
-
Free full text
-
Abstract
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.
-
3.
Changes of several brain receptor complexes in the cerebral cortex of patients with Alzheimer disease: probable new potential pharmaceutical targets.
Falsafi, SK, Roßner, S, Ghafari, M, Groessl, M, Morawski, M, Gerner, C, Lubec, G
Amino acids. 2014;(1):223-33
Abstract
Although Alzheimer disease (AD) has been linked to defects in major brain receptors, studies thus far have been limited to the determination of receptor subunits or specific ligand binding studies. However, the availability of current technology enables the determination and quantification of brain receptor complexes. Thus, we examined levels of native receptor complexes in the brains of patients with AD. Cortical tissue was obtained from control subjects (n = 12 females and 12 males) and patients with AD (n = 12 females and 12 males) within a 3-h postmortem time period. The tissues were kept frozen until further biochemical analyses. Membrane proteins were extracted and subsequently enriched by ultracentrifugation using a sucrose gradient. Membrane proteins were then electrophoresed onto native gels and immunoblotted using antibodies against individual brain receptors. We found that the levels were comparable for complexes containing GluR2, GluR3 and GluR4 as well as 5-HT1A. Moreover, the levels of complexes containing muscarinic AChR M1, NR1 and GluR1 were significantly increased in male patients with AD. Nicotinic AChRs 4 and 7 as well as dopaminergic receptors D1 and D2 were also increased in males and females with AD. These findings reveal a pattern of altered receptor complex levels that may contribute to the deterioration of the concerted activity of these receptors and thus result in cognitive deficits observed in patients with AD. It should be emphasised that receptor complexes function as working units rather than individual subunits. Thus, the receptor deficits identified may be relevant for the design of experimental therapies. Therefore, specific pharmacological modulation of these receptors is within the pharmaceutical repertoire.
-
4.
Whole exome sequencing identifies recessive PKHD1 mutations in a Chinese twin family with Caroli disease.
Hao, X, Liu, S, Dong, Q, Zhang, H, Zhao, J, Su, L
PloS one. 2014;(4):e92661
Abstract
BACKGROUND Mutations in PKHD1 cause autosomal recessive Caroli disease, which is a rare congenital disorder involving cystic dilatation of the intrahepatic bile ducts. However, the mutational spectrum of PKHD1 and the phenotype-genotype correlations have not yet been fully established. METHODS Whole exome sequencing (WES) was performed on one twin sample with Caroli disease from a Chinese family from Shandong province. Routine Sanger sequencing was used to validate the WES and to carry out segregation studies. We also described the PKHD1 mutation associated with the genotype-phenotype of this twin. RESULTS A combination of WES and Sanger sequencing revealed the genetic defect to be a novel compound heterozygous genotype in PKHD1, including the missense mutation c.2507 T>C, predicted to cause a valine to alanine substitution at codon 836 (c.2507T>C, p.Val836Ala), and the nonsense mutation c.2341C>T, which is predicted to result in an arginine to stop codon at codon 781 (c.2341C>T, p.Arg781*). This compound heterozygous genotype co-segregates with the Caroli disease-affected pedigree members, but is absent in 200 normal chromosomes. CONCLUSIONS Our findings indicate exome sequencing can be useful in the diagnosis of Caroli disease patients and associate a compound heterozygous genotype in PKHD1 with Caroli disease, which further increases our understanding of the mutation spectrum of PKHD1 in association with Caroli disease.
-
5.
Combined use of the novel biomarkers high-sensitivity troponin T and ST2 for heart failure risk stratification vs conventional assessment.
Lupón, J, de Antonio, M, Galán, A, Vila, J, Zamora, E, Urrutia, A, Bayes-Genis, A
Mayo Clinic proceedings. 2013;(3):234-43
Abstract
OBJECTIVE To assess an innovative multimarker strategy for risk stratification of death in a real-life ambulatory heart failure (HF) cohort. PATIENTS AND METHODS The study included 876 consecutive outpatients (median age, 70.3 years; left ventricular ejection fraction, 34%) between May 22, 2006, and July 7, 2010, prospectively followed up in a structured HF unit. A combination of biomarkers reflecting myocardial stretch (N-terminal pro-B-type natriuretic peptide [NT-proBNP]), myocyte injury (high-sensitivity cardiac troponin T [hs-cTnT]), and ventricular fibrosis and remodeling (high-sensitivity ST2 [hs-ST2]) were added to an assessment based on established mortality risk factors (age, sex, left ventricular ejection fraction, New York Heart Association functional class, diabetes mellitus, estimated glomerular filtration rate, ischemic etiology, sodium level, hemoglobin level, and pharmacologic treatment). RESULTS During median follow-up of 41.4 months, 311 patients died. The combined addition of hs-cTnT and hs-ST2 to the model yielded good measurements of performance (C statistic, 0.789; Bayesian information criterion, 3611; integrated discrimination improvement, 4.1 [95% CI, 2.5-5.6]; and net reclassification index, 13.9% [95% CI, 6.2-21.6]). Reclassification did not significantly benefit after NT-proBNP addition into the full model; some indices even worsened with all 3 biomarkers. Separate addition of NT-proBNP provided prognostic discrimination only in the subgroup of patients with either hs-cTnT or hs-ST2 levels below the cutoff points (hazard ratio, 2.97; 95% CI, 2.24-9.39; P<.001). CONCLUSION A multimarker strategy seems useful for stratifying risk in chronic HF. However, NT-proBNP in addition to the new-generation biomarkers hs-cTnT and hs-ST2 had a limited effect on risk stratification.
-
6.
Genetic variation in PEAR1 is associated with platelet aggregation and cardiovascular outcomes.
Lewis, JP, Ryan, K, O'Connell, JR, Horenstein, RB, Damcott, CM, Gibson, Q, Pollin, TI, Mitchell, BD, Beitelshees, AL, Pakzy, R, et al
Circulation. Cardiovascular genetics. 2013;(2):184-92
-
-
Free full text
-
Abstract
BACKGROUND- Aspirin or dual antiplatelet therapy with aspirin and clopidogrel is a standard therapy for patients who are at increased risk for cardiovascular events. However, the genetic determinants of variable response to aspirin (alone and in combination with clopidogrel) are not known. METHODS AND RESULTS- We measured ex vivo platelet aggregation before and after dual antiplatelet therapy in individuals (n=565) from the Pharmacogenomics of Anti-Platelet Intervention (PAPI) Study and conducted a genome-wide association study of drug response. Significant findings were extended by examining genotype and cardiovascular outcomes in 2 independent aspirin-treated cohorts: 227 percutaneous coronary intervention patients and 1000 patients of the International Verapamil SR/Trandolapril Study (INVEST) Genetic Substudy (INVEST-GENES). Results from the genome-wide association study revealed a strong association between single-nucleotide polymorphisms on chromosome 1q23 and post-dual antiplatelet therapyplatelet aggregation. Further genotyping revealed rs12041331 in the platelet endothelial aggregation receptor-1 (PEAR1) gene to be most strongly associated with dual antiplatelet therapy response (P=7.66×10(-9)). In white and black patients undergoing percutaneous coronary intervention, A-allele carriers of rs12041331 were more likely to experience a cardiovascular event or death compared with GG homozygotes (hazard ratio, 2.62; 95% confidence interval, 0.96-7.10; P=0.059; and hazard ratio, 3.97; 95% confidence interval, 1.10-14.31; P=0.035, respectively). In aspirin-treated INVEST-GENES patients, rs12041331 A-allele carriers had significantly increased risk of myocardial infarction compared with GG homozygotes (odds ratio, 2.03; 95% confidence interval, 1.01-4.09; P=0.048). CONCLUSION- Common genetic variation in PEAR1 may be a determinant of platelet response and cardiovascular events in patients on aspirin alone or in combination with clopidogrel. Clinical Trial Registration- URL: http://www.clinicaltrials.gov. Unique identifiers: NCT00799396 and NCT00370045.
-
7.
Transfer of folic acid inside the first-trimester gestational sac and the effect of maternal smoking.
Jauniaux, E, Johns, J, Gulbis, B, Spasic-Boskovic, O, Burton, GJ
American journal of obstetrics and gynecology. 2007;(1):58.e1-6
Abstract
OBJECTIVE The objective of the study was to investigate the transfer pathways of folic acid inside the first-trimester gestational sac and to evaluate the impact of maternal smoking. STUDY DESIGN Folate and cotinine levels were evaluated in maternal serum (n = 125) and coelomic fluid (n = 42), and immunostaining was used to identify folate receptors in placental villi, decidual tissue, and secondary yolk sacs from normal pregnancies at 6-12 weeks' gestation. RESULTS Folate receptors-alpha were found on the apical surface of syncytiotrophoblast, uterine glandular epithelial cells, and mesothelial layer of the yolk sac. Significantly higher (P < .05) median folate levels were found in maternal serum than in coelomic fluid. The median folate maternal serum and coelomic levels were significantly (P < .0001 and P < .005) lower in smokers, compared with nonsmokers. CONCLUSION Uterine glands and the secondary yolk sac play key roles in supplying folic acid to the developing fetus before the placental circulations are established, and maternal smoking does not seem to impair directly its transfer mechanism in early pregnancy.
-
8.
[The influence hypocaloric diet on induces of carbohydrate metabolism and concentration of leptin and soluble leptin receptor in the blood serum of the type 2 diabetic patients].
Klebanova, EM
Voprosy pitaniia. 2006;(4):29-31
Abstract
In this investigation shown the influence of traditional hypocaloric diet on concentration of leptin level and leptin receptor in type 2 diabetic patients. Our results show that diet therapy improves metabolic control, and as a result of a diet were normoglucaemia and decrease of leptin and leptin receptor level in type 2 diabetic patients.
-
9.
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).
-
10.
Effect of dieting on plasma leptin, soluble leptin receptor, adiponectin and resistin levels in healthy volunteers.
Wolfe, BE, Jimerson, DC, Orlova, C, Mantzoros, CS
Clinical endocrinology. 2004;(3):332-8
Abstract
OBJECTIVE Recent findings demonstrating important effects of the adipokines on metabolism, energy homeostasis and body weight regulation have prompted research on the possible role of negative energy balance in altering adipocytokine regulation. The goal of this study was to evaluate the effects of a hypocaloric diet in healthy normal-weight volunteers. An additional goal was to help clarify the contribution of restricted caloric intake to altered plasma adipokine levels in the eating disorders anorexia nervosa and bulimia nervosa. DESIGN Participants were studied before and after a 4-week reduced-calorie diet (1000-12000 kcal/day). patients Subjects included 15 healthy, normal-weight women (age 22 +/- 3 years). MEASUREMENTS Plasma concentrations of leptin, soluble leptin receptor protein (sOB-R), adiponectin, resistin, thyroid hormones and beta-hydroxybutyrate were determined following overnight fast before and after the 4-week reduced-calorie diet. RESULTS Subjects lost a mean of 3.4 +/- 2.1 kg in response to the reduced-calorie diet. The weight loss phase was associated with a 60.3% decrease in plasma leptin levels (P < 0.001), a 43.5% increase in sOB-R levels (P < 0.002) and a 16.2% decrease in plasma adiponectin levels (P < 0.04). There was no significant change in plasma resistin levels. CONCLUSIONS These results demonstrate that a modest decrease in energy intake sustained over several weeks may play an important role in altering levels of plasma leptin and sOB-R. The findings also provide preliminary evidence that, in contrast to previous results in obese subjects, caloric restriction with accompanying weight loss in healthy, normal-weight volunteers may lead to decreased circulating adiponectin levels. Additional studies will be needed to clarify the contribution of altered energy intake to abnormalities in cytokine levels in the eating disorders.