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1.
Effects of vitamin D supplementation on circulating concentrations of growth factors and immune-mediators in healthy women during pregnancy.
Khatiwada, A, Wolf, BJ, Mulligan, JK, Shary, JR, Hewison, M, Baatz, JE, Newton, DA, Hawrylowicz, C, Hollis, BW, Wagner, CL
Pediatric research. 2021;(3):554-562
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Abstract
BACKGROUND For the second aim of the Kellogg Foundation grant, this double-blind RCT investigated the impact of plasma vitamin D metabolite 25-hydroxyvitamin D (25(OH)D) on plasma immune-mediators during pregnancy. We hypothesized that higher 25(OH)D concentrations would associate with reduced pro-inflammatory and increased tolerogenic immune-mediator concentrations. METHODS Pregnant women enrolled at 10-14 weeks gestation were randomized to 400 or 4400 IU vitamin D3/day. Data on health, safety, circulating 25(OH)D, and 9 immune-mediators were collected at each trimester. Associations between immune-mediators and 25(OH)D at baseline and at second and third trimesters were examined. RESULTS Baseline TGF-β and second and third trimesters IFN-γ and IL-2 were associated with baseline 25(OH)D. Baseline immune-mediators were associated with immune-mediators at second and third trimesters for all immune-mediators except IL-5 and IL-10. Race was associated with baseline TGF-β, VEGF and IL-10 and with IL-10 at second and third trimesters. CONCLUSIONS Both treatment groups had increased 25(OH)D at second and third trimesters, greatest in the 4400 IU group. Though associations between baseline 25(OH)D and baseline TGF-β and second and third trimester IFN-γ and IL-2 were noted, vitamin D supplementation throughout pregnancy did not impact immune-mediators at later trimesters. Supplementing with vitamin D before conception conceivably influences immune-mediator responses during pregnancy. IMPACT In this vitamin D supplementation clinical trial, baseline (first trimester) but not increasing plasma 25(OH)D concentration impacted select plasma immune-mediator profiles in pregnant women. Baseline 25(OH)D was associated with baseline TGF-β and with IFN-γ and IL-2 at second and third trimesters. Baseline IFN-γ, CRP, TGF-β, TNF-α, VEGF, IL-2, and IL-4 were associated with concentrations at second and third trimesters for respective immune-mediators; however, 25(OH)D concentration at second and third trimesters were not. Some racial differences existed in immune-mediator concentrations at baseline and at second and third trimesters. This study assesses the impact of vitamin D supplementation on multiple immune-mediators in pregnant women of different racial/ethnic groups using longitudinal data from a relatively large randomized controlled trial. This study found that race was associated with baseline TGF-β, VEGF, and IL-10 and with IL-10 at second and third trimesters, a novel finding that sheds light where relationships were less well defined. The results of this study suggest that vitamin D supplementation before conception or early in pregnancy, rather than during pregnancy, may be necessary to significantly impact immune-mediator response. This study sets premise for future clinical trials to evaluate the effect of vitamin D supplementation before conception or prior to pregnancy.
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Intermittent Hypoxic Exposure with High Dose of Arginine Impact on Circulating Mediators of Tissue Regeneration.
Zembron-Lacny, A, Gramacki, A, Wawrzyniak-Gramacka, E, Tylutka, A, Hertmanowska, N, Kasperska, A, Czuba, M
Nutrients. 2020;(7)
Abstract
Intermittent exposure to hypoxia (IHE) increases production of reactive oxygen and nitrogen species which, as signalling molecules, participate in tissue injury-repair-regeneration cascade. The process is also stimulated by arginine whose bioavailability is a limiting factor for NO synthesis. The effects of IHE in combination with arginine (Arg) intake on myogenesis and angiogenesis mediators were examined in a randomized and placebo-controlled trial. Blood samples were collected from 38 elite athletes on the 1st, 7th and 14th days during the training camp. The oral doses of arginine (2 × 6 g/day) and/or IHE using hypoxicator GO2Altitude (IHE and Arg/IHE) were applied. Serum NO and H2O2 concentrations increased significantly and were related to muscle damage (CK activity >900 IU/mL) in IHE and Arg/IHE compared to placebo. The changes in NO and H2O2 elevated the levels of circulating growth factors such as HGF, IHG-1, PDGFBB, BDNF, VEGF and EPO. Modification of the lipid profile, especially reduced non-HDL, was an additional beneficial effect of hypoxic exposure with arginine intake. Intermittent hypoxic exposure combined with high-dose arginine intake was demonstrated to affect circulating mediators of injury-repair-regeneration. Therefore, a combination of IHE and arginine seems to be a potential therapeutic and non-pharmacological method to modulate the myogenesis and angiogenesis in elite athletes.
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Small-protein Enrichment Assay Enables the Rapid, Unbiased Analysis of Over 100 Low Abundance Factors from Human Plasma.
Harney, DJ, Hutchison, AT, Su, Z, Hatchwell, L, Heilbronn, LK, Hocking, S, James, DE, Larance, M
Molecular & cellular proteomics : MCP. 2019;(9):1899-1915
Abstract
Unbiased and sensitive quantification of low abundance small proteins in human plasma (e.g. hormones, immune factors, metabolic regulators) remains an unmet need. These small protein factors are typically analyzed individually and using antibodies that can lack specificity. Mass spectrometry (MS)-based proteomics has the potential to address these problems, however the analysis of plasma by MS is plagued by the extremely large dynamic range of this body fluid, with protein abundances spanning at least 13 orders of magnitude. Here we describe an enrichment assay (SPEA), that greatly simplifies the plasma dynamic range problem by enriching small-proteins of 2-10 kDa, enabling the rapid, specific and sensitive quantification of >100 small-protein factors in a single untargeted LC-MS/MS acquisition. Applying this method to perform deep-proteome profiling of human plasma we identify C5ORF46 as a previously uncharacterized human plasma protein. We further demonstrate the reproducibility of our workflow for low abundance protein analysis using a stable-isotope labeled protein standard of insulin spiked into human plasma. SPEA provides the ability to study numerous important hormones in a single rapid assay, which we applied to study the intermittent fasting response and observed several unexpected changes including decreased plasma abundance of the iron homeostasis regulator hepcidin.
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The Efficacy of Plasma Rich in Growth Factors for the Treatment of Alveolar Osteitis: A Randomized Controlled Trial.
King, EM, Cerajewska, TL, Locke, M, Claydon, NCA, Davies, M, West, NX
Journal of oral and maxillofacial surgery : official journal of the American Association of Oral and Maxillofacial Surgeons. 2018;(6):1150-1159
Abstract
PURPOSE To investigate the efficacy of plasma rich in growth factors (PRGF; BTI Biotechnology Institute, San Antonio, Spain) for the treatment of alveolar osteitis compared with a positive control (Alvogyl; Septodont, Maidstone, Kent, UK). MATERIALS AND METHODS This single-center, single-blinded, randomized, 2-treatment, parallel study was conducted in a UK dental hospital. All healthy adults who presented with alveolar osteitis after tooth extraction over a 3-month period were invited to participate. Each socket was randomized and treated with 1 of 2 treatment modalities, a test treatment (PRGF) or a positive control (Alvogyl). After treatment, patients were reviewed at 3 and 7 days by a second clinician blinded to the treatment given. Outcome measures included pain, exposed bone, inflammation, halitosis, dysgeusia, and quality-of-life assessment. RESULTS Thirty-eight patients with data from 44 sockets (22 in the PRGF group and 22 in the Alvogyl group) were analyzed. The PRGF group showed significantly faster bone coverage and significantly decreased inflammation and halitosis (P < .05) compared with the control group receiving Alvogyl. There was no significant difference for pain, quality-of-life measures, or dysgeusia between groups. CONCLUSION PRGF predictably treated alveolar osteitis after tooth extraction compared with the conventional standard treatment of Alvogyl, which has been used for many years. PRGF could be considered an alternative treatment for alveolar osteitis and indeed appears to have considerable advantages over Alvogyl.
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Six weeks of combined aerobic and resistance exercise using outdoor exercise machines improves fitness, insulin resistance, and chemerin in the Korean elderly: A pilot randomized controlled trial.
Kim, DI, Lee, DH, Hong, S, Jo, SW, Won, YS, Jeon, JY
Archives of gerontology and geriatrics. 2018;:59-64
Abstract
BACKGROUND The aim of this study was to investigate the effect of a six-week-long exercise program using outdoor exercise equipment on fitness, insulin resistance and adipocytokines among Korean elderly. METHODS A total of 47 participants were randomized into one of the following three groups; control, resistance exercise or combined exercise (aerobic and resistance exercise). The resistance exercise group completed three resistance types of exercise. The combined exercise group completed five exercises, including three resistance types of exercise and two aerobic types of exercise. Participants' body composition, fitness level, homeostasis model assessment of insulin resistance (HOMA-IR), and adipocytokines were measured at baseline and at the end of six weeks. RESULTS After six weeks of exercise training, participants in the combined exercise group exhibited significant reduction in insulin, HOMA-IR and chemerin levels, while significant reduction was observed in HOMA-IR only in the resistance exercise group compared with the control group. Meanwhile, six weeks of exercise training, whether resistance exercise alone or combined, significantly improved upper body muscular strength/endurance and physical function compared to the control group. CONCLUSIONS Six weeks of combined exercise using outdoor exercise equipment was effective in improving fitness, HOMA-IR, circulating chemerin levels, and other known risk factors of chronic diseases.
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Decrease in serum chemerin through aerobic exercise plus dieting and its association with mitigation of cardio-metabolic risk in obese female adolescents.
Liu, M, Lin, X, Wang, X
Journal of pediatric endocrinology & metabolism : JPEM. 2018;(2):127-135
Abstract
BACKGROUND The objective of this study was to determine the effects of a 4-week aerobic exercise plus dieting intervention on serum chemerin in obese female adolescents and its possible role in mitigating cardio-metabolic risk including glucose and lipid metabolism, central fat and inflammation. METHODS Fifty obese female adolescents were randomly divided into two groups: exercise plus dieting group (n=30) and dieting group (n=20). The participants in the exercise plus dieting group completed 4 weeks of moderate aerobic exercise combined with dieting, while the subjects in the dieting group undertook only dieting. Before and after the experiments, anthropometric index, parameters of glucose and lipid metabolism, serum chemerin and classic inflammatory indicators (C-reactive protein [CRP], tumor necrosis factor-α [TNF-α], interleukin-1β [IL-1β], IL-6, leptin and adiponectin) were measured. RESULTS Compared with the dieting group, a decrease in serum chemerin was found in the exercise plus dieting group, accompanied by significant improvements in anthropometric index, glucose and lipid metabolism and inflammatory factors. In addition, a higher serum chemerin level was found in obese adolescents with metabolic syndrome (MetS), and the disappearance of MetS induced by exercise plus dieting might be related to the decrease in chemerin. Correlation analysis showed the correlations of the decrease in chemerin with the changes in body fat, glucose and lipid metabolic index, leptin and adiponectin/leptin ratio. CONCLUSIONS This is the first report that as short a duration as 4-week aerobic exercise plus dieting decreased serum chemerin in obese female adolescents, which might be associated with the improvement in glucose and lipid metabolism, mitigation of inflammation and decrease in MetS incidence, thus lowering cardio-metabolic risk, while no health benefit resulted from slight dieting.
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Link between chemerin, central obesity, and parameters of the Metabolic Syndrome: findings from a longitudinal study in obese children participating in a lifestyle intervention.
Niklowitz, P, Rothermel, J, Lass, N, Barth, A, Reinehr, T
International journal of obesity (2005). 2018;(10):1743-1752
Abstract
OBJECTIVE Chemerin has been suggested as a potential link between obesity and associated comorbidities in humans. Therefore, we studied the relationships between chemerin, parameters of fat mass, and Metabolic Syndrome (MetS) in obese children before and after weight reduction. METHODS We determined chemerin, bioactive leptin (bioLep), BMI-SDS, waist circumference (WC), body fat based on skinfold measurements and bioimpedance analyses, lipids, transaminases, insulin resistance index HOMA, and blood pressure in 88 obese children participating in a lifestyle intervention at baseline and 1 year later. Furthermore, we determined chemerin concentrations in 23 normal-weight children. RESULTS Obese children demonstrated significantly (p < 0.001) higher chemerin concentrations compared to normal-weight children (96.2 ± 23.0 versus 63.1 ± 12.4 ng/ml). The chemerin concentrations were not related to age or gender. Prepubertal children had higher (p = 0.024) chemerin concentrations than pubertal children (71.0 ± 13.4 versus 58.0 ± 8.9 ng/ml). Weight loss was associated with a decrease of chemerin (-14.0 ± 22.0 ng/ml; p < 0.001) and an improvement of all parameters of the MetS. Chemerin was significantly related to BMI-SDS, WC, and bioLep in cross-sectional and longitudinal analyses. Chemerin and its changes were significantly related to insulin, HDL-cholesterol, triglycerides and their changes in multiple linear regression analyses adjusted to age, gender, pubertal stage, leptin and BMI. CONCLUSIONS Since chemerin was related to parameters of central fat mass and MetS both in cross-sectional and longitudinal analyses these findings suggest an impact of chemerin on factors of the MetS in obese children.
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The Efficacy of Imrecoxib and Celecoxib in Axial Spondyloarthritis and Their Influence on Serum Dickopff-Related Protein 1 (DKK-1) Levels.
Gao, GM, Li, YM, Zheng, XL, Jiang, DB, Zhang, LL, Xu, PH, Liu, SY, Zheng, ZH, Kan, QC
Medical science monitor : international medical journal of experimental and clinical research. 2017;:2985-2992
Abstract
BACKGROUND To observe and demonstrate therapeutic effects and side effects of two selective COX-2 inhibitors, imrecoxib and celecoxib, on patients with axial spondyloarthritis (axSpA) and observe the correlation between imaging scores and serum DKK-1 levels. MATERIAL AND METHODS Sixty patients with axSpA were randomly assigned to receive 200 mg imrecoxib or 200 mg celecoxib twice daily. Fifty-one patients who completed follow-up were included in the study. At baseline, week 4, and week 12, the clinical parameters, inflammatory markers (ESR, CRP), and adverse reactions were recorded. Serum DKK-1 levels were investigated by enzyme-linked immunosorbent assay. Radiographic scores were calculated by sacroiliac joint SPARCC (Spondyloarthritis Research Consortium of Canada) score method at baseline serum DKK-1 levels and week 12. RESULTS Patients in the imrecoxib group (n=25) and patients in the celecoxib group (n=26) were improved at week 4. At week 12, all clinical parameters and inflammatory markers were improved in the two groups and the differences was not statistically significant. Serum DKK-1 levels were decreased and the differences were not statistically significant. Serum DKK-1 levels in patients in the imrecoxib group at baseline were negatively correlated with all study parameters, while those in the celecoxib group had correlations with BASFI (r=-0.048, p=0.027) and Schober test (r=0.437, p=0.048), without any correlation with other clinical parameters or inflammatory markers. CONCLUSIONS Patients experienced significant improvement in disease activity, functional parameters, and inflammatory markers when treated with selective COX-2 inhibitors for 12 weeks, and the efficacy of imrecoxib was not inferior to celecoxib. Selective COX-2 inhibitors imrecoxib and celecoxib had no obvious effects on serum DKK-1 levels.
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Serum sclerostin and DKK1 in relation to exercise against bone loss in experimental bed rest.
Belavý, DL, Baecker, N, Armbrecht, G, Beller, G, Buehlmeier, J, Frings-Meuthen, P, Rittweger, J, Roth, HJ, Heer, M, Felsenberg, D
Journal of bone and mineral metabolism. 2016;(3):354-65
Abstract
The impact of effective exercise against bone loss during experimental bed rest appears to be associated with increases in bone formation rather than reductions of bone resorption. Sclerostin and dickkopf-1 are important inhibitors of osteoblast activity. We hypothesized that exercise in bed rest would prevent increases in sclerostin and dickkopf-1. Twenty-four male subjects performed resistive vibration exercise (RVE; n = 7), resistive exercise only (RE; n = 8), or no exercise (control n = 9) during 60 days of bed rest (2nd Berlin BedRest Study). We measured serum levels of BAP, CTX-I, iPTH, calcium, sclerostin, and dickkopf-1 at 16 time-points during and up to 1 year after bed rest. In inactive control, after an initial increase in both BAP and CTX-I, sclerostin increased. BAP then returned to baseline levels, and CTX-I continued to increase. In RVE and RE, BAP increased more than control in bed rest (p ≤ 0.029). Increases of CTX-I in RE and RVE did not differ significantly to inactive control. RE may have attenuated increases in sclerostin and dickkopf-1, but this was not statistically significant. In RVE there was no evidence for any impact on sclerostin and dickkopf-1 changes. Long-term recovery of bone was also measured and 6-24 months after bed rest, and proximal femur bone mineral content was still greater in RVE than control (p = 0.01). The results, while showing that exercise against bone loss in experimental bed rest results in greater bone formation, could not provide evidence that exercise impeded the rise in serum sclerostin and dickkopf-1 levels.
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Pro-permeability Factors in Diabetic Macular Edema; the Diabetic Macular Edema Treated With Ozurdex Trial.
Campochiaro, PA, Hafiz, G, Mir, TA, Scott, AW, Zimmer-Galler, I, Shah, SM, Wenick, AS, Brady, CJ, Han, I, He, L, et al
American journal of ophthalmology. 2016;:13-23
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Abstract
PURPOSE The Diabetic Macular Edema Treated with Ozurdex (DMEO) Trial measured aqueous pro-permeability factors (PPFs) in diabetic macular edema (DME) patients before and after injection of dexamethasone implant or vascular endothelial growth factor (VEGF)-neutralizing protein and correlated changes in levels with changes in excess foveal thickness (EFT) to identify potential PPFs contributing to DME. DESIGN Prospective, randomized crossover clinical trial. METHODS Twenty DME patients randomized to dexamethasone implant or VEGF-neutralizing protein had aqueous taps and spectral-domain optical coherence tomography (SDOCT) at baseline and every 4 weeks for 28 weeks. Aqueous levels of 55 vasoactive proteins were measured with protein array. Crossover at week 16 provided changes in protein levels after each intervention in all 20 patients. RESULTS After dexamethasone implant there was significant correlation between changes in levels of 13 vasoactive proteins with changes in EFT, including 3 known PPFs: angiopoietin-2 (r = 0.40, P = .001), hepatocyte growth factor (HGF; r = 0.31, P = .02), and endocrine gland-VEGF (EG-VEGF, r = 0.43, P < .001). Reduction of prolactin, insulin-like growth factor binding protein-3, and matrix metalloproteinase-9 correlated with edema reduction after injection of a VEGF-neutralizing protein as well as dexamethasone implant, suggesting their modulation is likely secondary to changes in edema rather than causative. CONCLUSIONS Correlation of edema reduction with reduction in the PPFs angiopoietin-2, HGF, and EG-VEGF provides potential insight into the multifactorial molecular mechanism by which dexamethasone implants reduce edema and suggest that additional study is needed to investigate the contributions of these 3 factors to chronic DME.