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Circulating semaphorin-4D and plexin-B1 levels in postmenopausal women with low bone mass: the 3-month effect of zoledronic acid, denosumab or teriparatide treatment.
Anastasilakis, AD, Polyzos, SA, Makras, P, Gkiomisi, A, Sakellariou, G, Savvidis, M, Papatheodorou, A, Kokkoris, P, Terpos, E
Expert opinion on therapeutic targets. 2015;(3):299-306
Abstract
OBJECTIVE The evaluation of circulating semaphorin-4D (sema4D) and plexin-B1 in postmenopausal women with low bone mass and the effect of antiresorptive or osteoanabolic treatment. METHODS Serum samples were obtained from postmenopausal women with low bone mass at baseline and 3 months after zoledronic acid infusion (n = 30), denosumab injection (n = 30) or teriparatide initiation (n = 28) and from controls matched for age, age at menopause and body mass index (n = 30) at the same time points. MAIN OUTCOME MEASURES Circulating sema4D and plexin-B1. RESULTS Circulating sema4D increased following denosumab (p = 0.026), whereas decreased following teriparatide (p = 0.013). Sema4D/plexin-B1 ratio increased following denosumab (p = 0.004). At baseline, sema4D and plexin-B1 levels were higher in patients pre-treated with bisphosphonates compared to naïve ones (p < 0.001 and p = 0.001, respectively). In bivariate correlations sema4D was inversely correlated with serum carboxyterminal telopeptide of type 1 collagen (rs -0.282, p = 0.002), intact parathyroid hormone (rs -0.388, p < 0.001) and 25(OH)D (rs -0.316, p < 0.001), whereas there was a trend towards correlation with lumbar spine bone mineral density (rs -0.191, p = 0.053). CONCLUSIONS Sema4D levels are independently associated with previous bisphosphonate treatment, intact parathyroid hormone and 25(OH)D levels. Denosumab and teriparatide seem to exert an opposite effect on circulating sema4D levels. Further studies are needed to evaluate whether sema4D mediates the coupling effect that occurs following both antiresorptive and osteoanabolic treatment.
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The influence of very-low-calorie-diet on serum leptin, soluble leptin receptor, adiponectin and resistin levels in obese women.
Anderlová, K, Kremen, J, Dolezalová, R, Housová, J, Haluzíková, D, Kunesová, M, Haluzík, M
Physiological research. 2006;(3):277-283
Abstract
The aim of our study was to determine whether adipocyte-derived hormones leptin, adiponectin and resistin contribute to the improvement of insulin sensitivity after very-low calorie diet (VLCD). Therefore, serum levels of these hormones were measured in fourteen obese females before and after three weeks VLCD and in seventeen age- and sex-matched healthy controls. Body mass index, HOMA index, serum insulin and leptin levels in obese women before VLCD were significantly higher than in control group (BMI 48.01+/-2.02 vs. 21.38+/-0.42 kg/m(2), HOMA 10.72+/-2.03 vs. 4.69+/-0.42, insulin 38.63+/-5.10 vs. 18.76+/-1.90 microIU/ml, leptin 77.87+/-8.98 vs. 8.82+/-1.52 ng/ml). In contrast, serum adiponectin and soluble leptin receptors levels were significantly lower in obese women before VLCD than in the control group. No differences were found in serum glucose and resistin levels between the obese group before VLCD and the control group. VLCD significantly decreased BMI, HOMA index, serum glucose, insulin and leptin levels and increased soluble leptin receptor levels. The changes in serum adiponectin and resistin levels in obese women after VLCD did not reach statistical significance. We conclude that leptin and soluble leptin receptor levels were affected by VLCD while adiponectin and resistin concentrations were not. Therefore, other mechanisms rather than changes in the endocrine function of the adipose tissue are probably involved in the VLCD-induced improvement of insulin sensitivity.
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TLR4 is lower in resistance-trained older women and related to inflammatory cytokines.
McFarlin, BK, Flynn, MG, Campbell, WW, Stewart, LK, Timmerman, KL
Medicine and science in sports and exercise. 2004;(11):1876-83
Abstract
INTRODUCTION/PURPOSE Regular exercise may offset age-associated increases in inflammatory cytokines and reduce the risk of developing diseases with an inflammatory etiology by exerting "anti-inflammatory" effects. Toll-like receptor 4 (TLR4) signaling stimulates inflammatory cytokine production, and may explain the "anti-inflammatory" effect attributed to regular exercise. Therefore, the purpose of the present study was to compare the effect of acute (3 sets, 9 exercises, 10 repetitions at 80% of the 1-repetition maximum) and chronic resistance exercise on TLR4 and inflammatory cytokines. METHODS Venous blood samples were collected from trained (TR, N = 10) and untrained (UT, N = 10) older (65-80 yr) postmenopausal women: before (PRE), immediately post (POST), and 2 h (2H), 6 h (6H), and 24 h (24H) after completion of exercise. Cell-surface expression of TLR4 (two-color immunofluorescent cytometry), LPS (25 microg x mL(-1))-stimulated cytokine production (ELISA), plasma cytokines (ELISA), and mRNA expression of TLR4 and cytokines (RT-PCR) were determined for each sample. RESULTS TR had 124% less cell-surface TLR4 expression than UT (P < 0.05). A significant time effect was found for LPS-stimulated IL-6, IL-1beta, and TNF-alpha, where 6H was significantly greater than all other samples. No significant effects were found for plasma (IL-6 and TNF-alpha) or mRNA expression (IL-6, TNF-alpha, and IL-1beta) of inflammatory cytokines. When subjects were grouped according to cell-surface TLR4 expression (HI and LO), LPS-stimulated TNF-alpha (302%), IL-1beta (209%), and IL-6 (167%) production was greater for HI than LO (P < 0.05). CONCLUSION Regularly exercising older women expressed less cell-surface TLR4 but did not have lower plasma levels or produce less LPS-stimulated inflammatory cytokines at rest or in response to a single bout of resistance exercise. TLR4 changes may explain the "anti-inflammatory" effect that has recently been attributed to chronic (2x wk for previous 24 months) resistance exercise training.
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Peripheral blood mononuclear cell expression of toll-like receptors and relation to cytokine levels in cirrhosis.
Riordan, SM, Skinner, N, Nagree, A, McCallum, H, McIver, CJ, Kurtovic, J, Hamilton, JA, Bengmark, S, Williams, R, Visvanathan, K
Hepatology (Baltimore, Md.). 2003;(5):1154-64
Abstract
Activation of macrophages by endotoxin is assumed responsible for increased circulating tumor necrosis factor alpha (TNF-alpha) and soluble TNF receptor (sTNFR) levels in cirrhosis. Relevant to this is expression of Toll-like receptor (TLR) 4 and TLR2, which is critically involved in production of TNF-alpha in response to endotoxin and Gram-positive microbial stimuli, respectively. The first studies on this in cirrhosis are reported here. In 36 cirrhotic patients and 32 controls, we measured (1) circulating endotoxin, TNF-alpha, and sTNFR levels; (2) peripheral blood mononuclear cell (PBMC) expression of TLR4 and TLR2, and (3) in vitro TNF-alpha production by PBMCs stimulated with endotoxin or Staphylococcus aureus enterotoxin B (SEB). PBMC expression of TLR2, circulating TNF-alpha levels, and in vitro TNF-alpha production were reassessed after supplementation with a synbiotic regimen known to increase intestinal levels of Gram-positive bacteria. Endotoxin, TNF-alpha, and sTNFR levels were significantly increased in cirrhosis. Endotoxin levels did not correlate significantly with other parameters. PBMC expression of TLR2 but not TLR4 was significantly up-regulated in cirrhosis and correlated significantly with serum TNF-alpha and sTNFR levels. In vitro TNF-alpha production by PBMCs stimulated by SEB was significantly blunted. Supplementation with the synbiotic regimen resulted in significant up-regulation of PBMC expression of TLR2. Serum TNF-alpha levels were further increased and in vitro TNF-alpha production further reduced in most patients. In conclusion, up-regulation of PBMC expression of TLR2 but not TLR4 occurs in cirrhosis, which implies, contrary to previous assumptions, an important stimulatory role for Gram-positive microbial components but not endotoxin. TLR2 likely contributes to increased circulating TNF-alpha and sTNFR levels in cirrhosis.