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Differential effects of testosterone on circulating neutrophils, monocytes, and platelets in men: Findings from two trials.
Gagliano-Jucá, T, Pencina, KM, Guo, W, Li, Z, Huang, G, Basaria, S, Bhasin, S
Andrology. 2020;(5):1324-1331
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Abstract
BACKGROUND Testosterone treatment increases erythrocytes in men, but its effects on leukocyte and platelet counts are unknown and could affect its safety. OBJECTIVE To determine whether testosterone affects circulating leukocytes and platelets in men. METHODS Secondary analyses of two randomized testosterone trials were performed: the 5α-reductase (5aR) and OPTIMEN trials. In 5aR trial, 102 healthy men, 21-50 years (mean age 38), received a long-acting GnRH agonist, and 50, 125, 300, or 600 mg/week testosterone enanthate (TE) plus placebo or 2.5 mg/ day dutasteride for 20 weeks. In OPTIMEN, 78 functionally limited men, ≥65 years (mean age 72) with protein intake ≤ 0.83 g kg-1 day-1 , were randomized to controlled diets with 0.8 g kg-1 day-1 protein or 1.3 g kg-1 day-1 protein plus placebo or TE (100 mg/week) for 6 months. Changes from baseline in total and differential leukocyte count, and platelet count were evaluated. RESULTS In 5aR, testosterone administration was associated with increases in total leukocyte (estimated change from baseline 40, 490, 1230, and 1280 cells/µL, P < .001), neutrophil (65.1, 436.1, 1177.2, and 1192.2 cells/µL, P < .001), monocyte (-20.2, 24.5, 90.6, and 143.9 cells/µL, P < .001), platelet (-7.3, 8.4, 8.7, and 8.9 × 103 cells/µL, P = .033), and erythrocyte counts. Testosterone did not affect absolute lymphocyte count. Similar increase in total leukocyte count was observed with testosterone treatment in OPTIMEN (change 0.77 × 103 cells/µL, P vs placebo = 0.004). CONCLUSIONS Testosterone administration in men differentially increases neutrophil and monocyte counts. These findings, together with its erythropoietic effects, suggest that testosterone promotes the differentiation of hematopoietic progenitors into the myeloid lineage. These findings have potential mechanistic, therapeutic, and safety implications.
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Oral Ketone Supplementation Acutely Increases Markers of NLRP3 Inflammasome Activation in Human Monocytes.
Neudorf, H, Durrer, C, Myette-Cote, E, Makins, C, O'Malley, T, Little, JP
Molecular nutrition & food research. 2019;(11):e1801171
Abstract
SCOPE Cell culture studies indicate that the ketone β-hydroxybutyrate (β-OHB) directly inhibits the NLRP3 inflammasome, a key regulator of inflammation. However, direct evidence demonstrating this effect in humans is lacking. METHODS AND RESULTS To determine the effects of acutely raising blood β-OHB in healthy humans, two separate randomized double-blind placebo-controlled experiments are conducted using similar methods but each employed different exogenous ketone supplements. Participants' blood β-OHB is directly elevated by ketone salts (0.3 g β-OHB per kg; Study 1, N = 10 males) or ketone monoester (0.482 g β-OHB per kg; Study 2, N = 18, equal males/females). Markers of NLRP3 inflammasome activation include caspase-1, IL-1β secretion, and IL1B and NLRP3 mRNA in LPS-stimulated whole blood collected at the baseline and 30 minutes following supplementation. Caspase-1 activation increases after ketone salt (Study 1: condition × time interaction, p = 0.012) and monoester supplementation (Study 2: condition × time interaction, p = 0.016) compared to placebo. IL-1β secretion increases (main effect of condition, p = 0.024; Study 2) while IL1B and NLRP3 mRNA remain unchanged. CONCLUSION Measures of NLRP3 activation increases when blood β-OHB is elevated using ketone supplements, suggesting that increasing β-OHB exogenously may have unintended effects that augment inflammatory activation.
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Brief Report: Zinc Supplementation and Inflammation in Treated HIV.
Dirajlal-Fargo, S, Yu, J, Kulkarni, M, Sattar, A, Funderburg, N, Barkoukis, H, Mccomsey, GA
Journal of acquired immune deficiency syndromes (1999). 2019;(3):275-280
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Abstract
OBJECTIVE In this study, we explored the effect of zinc supplementation on markers of inflammation and monocyte activation in antiretroviral therapy-treated HIV infection. METHODS This is a phase I open-labeled randomized double-arm study, exploring the efficacy and safety of zinc supplementation on inflammation in ≥18-year-old people living with HIV in the US, on stable antiretroviral therapy and with zinc levels ≤75 µg/dL in the last 60 days. Patients were randomized 1:1 to zinc gluconate capsules at a dose of 45 mg (low-dose), or 90 mg (high-dose) elemental zinc daily for 16 weeks. We assessed inflammatory and gut integrity biomarkers at baseline and 16 weeks. RESULTS Overall, a total of 52 participants were enrolled (25 participants in the low-dose arm and 27 participants in the high-dose arm). Median (Interquartile range) age was 49 (38, 60) years, 77% were men and 73% were African Americans. At baseline, median zinc levels were 73 (64, 86) µg/dL. Median circulating zinc levels increased to 91 µg/dL in the low-dose arm and to 100 µg/dL in the high-dose arm. Overall, 48%-60% of participants experienced a reduction in biomarkers levels. The margin of reduction ranged between 8% and 21%. This change was meaningful with large effect size (Cohen D ranging from 5 to 19). CONCLUSIONS In this pilot study, we found that zinc supplementation is effective at increasing circulating zinc levels. In addition, our findings provide novel data suggesting that zinc can affect a biological signature in people living with HIV and modulate biomarkers associated with clinical comorbidities.
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A Single 48 mg Sucralose Sip Unbalances Monocyte Subpopulations and Stimulates Insulin Secretion in Healthy Young Adults.
Gómez-Arauz, AY, Bueno-Hernández, N, Palomera, LF, Alcántara-Suárez, R, De León, KL, Méndez-García, LA, Carrero-Aguirre, M, Manjarrez-Reyna, AN, Martínez-Reyes, CP, Esquivel-Velázquez, M, et al
Journal of immunology research. 2019;:6105059
Abstract
Sucralose is a noncaloric artificial sweetener that is widely consumed worldwide and has been associated with alteration in glucose and insulin homeostasis. Unbalance in monocyte subpopulations expressing CD11c and CD206 hallmarks metabolic dysfunction but has not yet been studied in response to sucralose. Our goal was to examine the effect of a single sucralose sip on serum insulin and blood glucose and the percentages of classical, intermediate, and nonclassical monocytes in healthy young adults subjected to an oral glucose tolerance test (OGTT). This study was a randomized, placebo-controlled clinical trial. Volunteers randomly received 60 mL water as placebo (n = 20) or 48 mg sucralose dissolved in 60 mL water (n = 25), fifteen minutes prior to an OGTT. Blood samples were individually drawn every 15 minutes for 180 minutes for quantifying glucose and insulin concentrations. Monocyte subsets expressing CD11c and CD206 were measured at -15 and 180 minutes by flow cytometry. As compared to controls, volunteers receiving sucralose exhibited significant increases in serum insulin at 30, 45, and 180 minutes, whereas blood glucose values showed no significant differences. Sucralose consumption caused a significant 7% increase in classical monocytes and 63% decrease in nonclassical monocytes with respect to placebo controls. Pearson's correlation models revealed a strong association of insulin with sucralose-induced monocyte subpopulation unbalance whereas glucose values did not show significant correlations. Sucralose ingestion decreased CD11c expression in all monocyte subsets and reduced CD206 expression in nonclassical monocytes suggesting that sucralose does not only unbalance monocyte subpopulations but also alter their expression pattern of cell surface molecules. This work demonstrates for the first time that a 48 mg sucralose sip increases serum insulin and unbalances monocyte subpopulations expressing CD11c and CD206 in noninsulin-resistant healthy young adults subjected to an OGTT. The apparently innocuous consumption of sucralose should be reexamined in light of these results.
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BCG Vaccination Protects against Experimental Viral Infection in Humans through the Induction of Cytokines Associated with Trained Immunity.
Arts, RJW, Moorlag, SJCFM, Novakovic, B, Li, Y, Wang, SY, Oosting, M, Kumar, V, Xavier, RJ, Wijmenga, C, Joosten, LAB, et al
Cell host & microbe. 2018;(1):89-100.e5
Abstract
The tuberculosis vaccine bacillus Calmette-Guérin (BCG) has heterologous beneficial effects against non-related infections. The basis of these effects has been poorly explored in humans. In a randomized placebo-controlled human challenge study, we found that BCG vaccination induced genome-wide epigenetic reprograming of monocytes and protected against experimental infection with an attenuated yellow fever virus vaccine strain. Epigenetic reprogramming was accompanied by functional changes indicative of trained immunity. Reduction of viremia was highly correlated with the upregulation of IL-1β, a heterologous cytokine associated with the induction of trained immunity, but not with the specific IFNγ response. The importance of IL-1β for the induction of trained immunity was validated through genetic, epigenetic, and immunological studies. In conclusion, BCG induces epigenetic reprogramming in human monocytes in vivo, followed by functional reprogramming and protection against non-related viral infections, with a key role for IL-1β as a mediator of trained immunity responses.
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Resistance Exercise Selectively Mobilizes Monocyte Subsets: Role of Polyphenols.
Jajtner, AR, Townsend, JR, Beyer, KS, Varanoske, AN, Church, DD, Oliveira, LP, Herrlinger, KA, Radom-Aizik, S, Fukuda, DH, Stout, JR, et al
Medicine and science in sports and exercise. 2018;(11):2231-2241
Abstract
PURPOSE To examine the impact of polyphenol supplementation on the recruitment, mobilization, and activation of monocyte subsets after resistance exercise. METHODS Thirty-eight recreationally active males (22.1 ± 3.1 yr; 173.9 ± 7.9 cm; 77.8 ± 14.5 kg) were assigned to 28 d of polyphenol blend (PPB) supplementation, placebo (PL), or control (CON). Blood samples were obtained before (PRE) postresistance exercise, immediately (IP) postresistance exercise, 1 h (1H) postresistance exercise, 5 h (5H) postresistance exercise, 24 h (24H) postresistance exercise, and 48 h (48H) postresistance exercise (PPB/PL) or rest (CON). Fine-needle biopsies were obtained from the vastus lateralis at PRE, 1H, 5H, and 48H. Circulating concentrations of macrophage chemoattractant protein-1 (MCP-1) and fractalkine, as well as intramuscular MCP-1 were analyzed via multiplex assay. Changes in the proportions and expression of CD11b on monocyte subsets were assessed via flow cytometry. RESULTS Circulating MCP-1 increased in PPB and PL at IP with further increases at 5H. Intramuscular MCP-1 was increased at 1H, 5H, and 48H in all groups. Classical monocyte proportions were reduced in PPB and PL at IP, and increased at 1H. Nonclassical monocytes were increased in PPB and PL at IP, whereas intermediate monocytes were increased at IP, and reduced at 1H. Intermediate monocytes were increased in PPB at 24H and 48H. CD11b expression was reduced on PPB compared with PL and CON at PRE on intermediate and nonclassical monocytes. CONCLUSIONS Resistance exercise may elicit selective mobilization of intermediate monocytes at 24H and 48H, which may be mediated by tissue damage. Additionally, polyphenol supplementation may suppress CD11b expression on monocyte subsets at rest.
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The comparison of knee osteoarthritis treatment with single-dose bone marrow-derived mononuclear cells vs. hyaluronic acid injections.
Goncars, V, Jakobsons, E, Blums, K, Briede, I, Patetko, L, Erglis, K, Erglis, M, Kalnberzs, K, Muiznieks, I, Erglis, A
Medicina (Kaunas, Lithuania). 2017;(2):101-108
Abstract
OBJECTIVE The aim of this study was to compare treatment methods of the knee joint degenerative osteoarthritis, using autologous bone marrow-derived mononuclear cells and hyaluronic acid injections and observe prevalence of adverse effects in both groups. MATERIALS AND METHODS A prospective randomized controlled clinical trial was carried out. The analysis of pain and changes in osteoarthritis symptoms after a single intra-articular bone marrow-derived mononuclear cell injection into the knee joint in the Kellgren-Lawrence stage II-III osteoarthritis during the 12-month period were performed. The results were compared with the control group treated routinely by hyaluronic acid injections therapy. A therapy group of patients (n=28) received single bone marrow-derived mononuclear cell intra-articular injections. A control group of patients (n=28) was treated with a total of three sodium hyaluronate intra-articular injections each one performed a week apart. The clinical results were obtained using the Knee Osteoarthritis Outcome Score (KOOS) and the Knee Society Score (KSS) before and 3, 6, and 12 months after injection. RESULTS A statistically significant improvement was observed in the mononuclear cell group over the starting point in all scores. At the endpoint at month 12, the KOOS score improved significantly (P<0.05) on the pain subscale (+25.44), activity and daily living subscale (+21.36), quality of life subscale (+28.83), and total KOOS (+18.25). The KSS score also demonstrated a significant improvement on the symptoms subscale (+25.42) and the function subscale (+38.32) (P<0.001). The KOOS symptoms and sports subscales improved without statistical significance. The difference between the control group treated with hyaluronic acid versus the bone marrow-derived mononuclear cells group at time points 6 and 12 months demonstrated a statistically significant (P<0.05) superiority in the KOOS pain subscale over the hyaluronic acid group. In both groups serious adverse effects were not observed. CONCLUSIONS The intra-articular injection of bone marrow-derived mononuclear cells is a safe manipulation with no side effects during the 12-month period. This treatment provides statistically significant clinical improvement between the starting point and 1, 3, 6, and 12 months after. When compared to hyaluronic acid treatment, better pain relief in the long-term period of mononuclear cell group was observed.
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Weight loss achieved using an energy restriction diet with normal or higher dietary protein decreased the number of CD14++CD16+ proinflammatory monocytes and plasma lipids and lipoproteins in middle-aged, overweight, and obese adults.
Kim, JE, Lin, G, Zhou, J, Mund, JA, Case, J, Campbell, WW
Nutrition research (New York, N.Y.). 2017;:75-84
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Abstract
Monocytes are involved in immune responses, and specific monocyte subpopulations (MS) that express intermediate to high levels of CD16 are associated with obesity and cardiovascular events. Consuming high protein (HP) when dieting improves body composition and cardiometabolic health outcomes, but whether HP affects MS during weight loss remains unknown. We assessed the effect of HP on energy restriction (ER)-induced changes in MS in overweight and obese adults. The relations between MS and plasma lipids and lipoproteins were also examined. We hypothesized that, independent of protein intake, ER-induced weight loss would decrease the numbers of MS and that MS and plasma lipids and lipoproteins would be related. Thirty-two adults (age 52 ± 1 years, body mass index 31.3 ± 0.5 kg/m2, means ± S.E.) consumed either a normal protein (n=18) or HP (n=14) (0.8 vs 1.5 g•kg-1•d-1 protein) ER diet (750-kcal/d [3138-kJ/d] deficit) for 16 weeks. The HP diet included 0.7 g•kg-1•d-1 of milk protein isolate. Fasting plasma lipids, lipoproteins, and the numbers of MS were analyzed. Over time, independent of protein intake, CD14++CD16+ cell number decreased, whereas CD14dimCD16++, CD14+CD16+, and CD14+CD16- cell numbers remained unchanged. CD14dimCD16++ cell number was negatively associated with total cholesterol (TC) and triglyceride, while CD14++CD16+ cell number was positively associated with TC, low-density lipoprotein cholesterol (LDL), TC to high-density lipoprotein cholesterol (HDL) ratio, and LDL to HDL ratio. Weight loss achieved while consuming an ER diet with either normal or high protein may improve immunity by partially decreasing proinflammatory monocytes. Associations between MS and plasma lipids and lipoproteins are confirmed in overweight and obese adults.
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Neutrophil and Monocyte Bactericidal Responses to 10 Weeks of Low-Volume High-Intensity Interval or Moderate-Intensity Continuous Training in Sedentary Adults.
Bartlett, DB, Shepherd, SO, Wilson, OJ, Adlan, AM, Wagenmakers, AJM, Shaw, CS, Lord, JM
Oxidative medicine and cellular longevity. 2017;:8148742
Abstract
Neutrophils and monocytes are key components of the innate immune system that undergo age-associated declines in function. This study compared the impact of high-intensity interval training (HIIT) and moderate-intensity continuous training (MICT) on immune function in sedentary adults. Twenty-seven (43 ± 11 years) healthy sedentary adults were randomized into ten weeks of either a HIIT (>90% maximum heart rate) or MICT (70% maximum heart rate) group training program. Aerobic capacity (VO2peak), neutrophil and monocyte bacterial phagocytosis and oxidative burst, cell surface receptor expression, and systemic inflammation were measured before and after the training. Total exercise time commitment was 57% less for HIIT compared to that for MICT while both significantly improved VO2peak similarly. Neutrophil phagocytosis and oxidative burst and monocyte phagocytosis and percentage of monocytes producing an oxidative burst were improved by training similarly in both groups. Expression of monocyte but not neutrophil CD16, TLR2, and TLR4 was reduced by training similarly in both groups. No differences in systemic inflammation were observed for training; however, leptin was reduced in the MICT group only. With similar immune-enhancing effects for HIIT compared to those for MICT at 50% of the time commitment, our results support HIIT as a time efficient exercise option to improve neutrophil and monocyte function.
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Changes in oxidized lipids drive the improvement in monocyte activation and vascular disease after statin therapy in HIV.
Hileman, CO, Turner, R, Funderburg, NT, Semba, RD, McComsey, GA
AIDS (London, England). 2016;(1):65-73
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BACKGROUND Oxidative stress plays a significant role in atherosclerosis development. HIV infection has been linked with heightened cardiovascular disease risk. HMG-CoA reductase inhibitors may reduce oxidative stress and subsequently subclinical vascular disease in HIV. DESIGN/METHODS This is a randomized, placebo-controlled trial to evaluate the effect of rosuvastatin in HIV-infected adults on stable antiretroviral therapy with low-density lipoprotein less than 130 mg/dl and increased inflammation or T-cell activation on subclinical vascular disease. Changes over 48 weeks in oxidative stress markers, oxidized low-density lipoprotein (oxLDL) and F2-isoprostane/creatinine ratio (F2-IsoP/Cr), were compared between groups. Spearman correlation and multivariable linear regression were used to evaluate relationships between changes in markers of oxidative stress, inflammation and monocyte activation and carotid intima media thickness (CIMT). RESULTS One hundred and forty-seven adults enrolled (72 to rosuvastatin and 75 to placebo). In the rosuvastatin group, oxLDL decreased significantly over 24 weeks compared to placebo [mean absolute change in log-oxLDL for rosuvastatin -0.2 ± 0.468 log U/l (P < 0.001 within-group) vs. placebo -0.018 ± 0.456 log U/l (P = 0.83 within-group); P = 0.004 between groups] and this change was linked with changes in soluble CD14 and proportion of patrolling monocytes (CD14dimCD16). Although oxLDL levels increased after initially declining and were not different from placebo at week 48, the early improvement in oxLDL was associated with improved CIMT at week 48. Changes in F2-IsoP/Cr were not significant between groups. CONCLUSION Rosuvastatin decreases oxLDL levels early after initiation and is associated with decreased monocyte activation. Early improvement in oxLDL is linked with improved CIMT in treated HIV infection.