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Beneficial effects of novel aureobasidium pullulans strains produced beta-1,3-1,6 glucans on interleukin-6 and D-dimer levels in COVID-19 patients; results of a randomized multiple-arm pilot clinical study.
Raghavan, K, Dedeepiya, VD, Suryaprakash, V, Rao, KS, Ikewaki, N, Sonoda, T, Levy, GA, Iwasaki, M, Senthilkumar, R, Preethy, S, et al
Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie. 2022;:112243
Abstract
OBJECTIVE In this pilot clinical study, we report the beneficial effects of beta glucans derived from two strains AFO-202 and N-163 of a black yeast Aureobasidium pullulans on the biomarkers for cytokine storm and coagulopathy in COVID-19 patients. METHODS A total of 24 RT-PCR positive COVID-19 patients were recruited and randomly divided into three groups (Gr): Gr. 1 control (n = 8) - Standard treatment; Gr. 2: Standard treatment + AFO-202 beta glucan (n = 8); and Gr. 3, Standard treatment + combination of AFO-202 and N-163 beta glucans (n = 8) for 30 days. RESULTS There was no mortality or requirement of ventilation of the subjects in any of the groups. There was a decrease in D-Dimer values (751 ng/ml to 143.89 ng/ml) and IL-6 values (7.395-3.16 pg/ml) in Gr. 1 in 15 days but the levels increased to abnormal levels on day 30 (D-Dimer: 202.5 ng/ml; IL-6 55.37 pg/ml); which steadily decreased up to day 30 in groups 2 (D-dimer: 560.99 ng/dl to 79.615; IL-6: 26.18-3.41 pg/ml) and 3 (D-dimer: 1614 ng/dl to 164.25 ng/dl; IL-6: 6.25-0.5 pg/ml). The same trend was observed with ESR. LCR and LeCR increased while NLR decreased significantly in Gr. 3. CD4 + and CD8 + T cell count showed relatively higher increase in Gr.3. There was no difference in CRP within the groups. CONCLUSION As these beta glucans are well known food supplements with a track record for safety, larger multi-centric clinical studies are recommended to validate their use as an adjunct in the management of COVID-19 and the ensuing long COVID-19 syndrome.
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Baseline Interleukin-6 and -8 predict response and survival in patients with advanced hepatocellular carcinoma treated with sorafenib monotherapy: an exploratory post hoc analysis of the SORAMIC trial.
Öcal, O, Schütte, K, Kupčinskas, J, Morkunas, E, Jurkeviciute, G, de Toni, EN, Ben Khaled, N, Berg, T, Malfertheiner, P, Klümpen, HJ, et al
Journal of cancer research and clinical oncology. 2022;(2):475-485
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PURPOSE To explore the potential correlation between baseline interleukin (IL) values and overall survival or objective response in patients with hepatocellular carcinoma (HCC) receiving sorafenib. METHODS A subset of patients with HCC undergoing sorafenib monotherapy within a prospective multicenter phase II trial (SORAMIC, sorafenib treatment alone vs. combined with Y90 radioembolization) underwent baseline IL-6 and IL-8 assessment before treatment initiation. In this exploratory post hoc analysis, the best cut-off points for baseline IL-6 and IL-8 values predicting overall survival (OS) were evaluated, as well as correlation with the objective response. RESULTS Forty-seven patients (43 male) with a median OS of 13.8 months were analyzed. Cut-off values of 8.58 and 57.9 pg/mL most effectively predicted overall survival for IL-6 and IL-8, respectively. Patients with high IL-6 (HR, 4.1 [1.9-8.9], p < 0.001) and IL-8 (HR, 2.4 [1.2-4.7], p = 0.009) had significantly shorter overall survival than patients with low IL values. Multivariate analysis confirmed IL-6 (HR, 2.99 [1.22-7.3], p = 0.017) and IL-8 (HR, 2.19 [1.02-4.7], p = 0.044) as independent predictors of OS. Baseline IL-6 and IL-8 with respective cut-off values predicted objective response rates according to mRECIST in a subset of 42 patients with follow-up imaging available (IL-6, 46.6% vs. 19.2%, p = 0.007; IL-8, 50.0% vs. 17.4%, p = 0.011). CONCLUSION IL-6 and IL-8 baseline values predicted outcomes of sorafenib-treated patients in this well-characterized prospective cohort of the SORAMIC trial. We suggest that the respective cut-off values might serve for validation in larger cohorts, potentially offering guidance for improved patient selection.
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Expression of NF-κB, IL-6, and IL-10 genes, body composition, and hepatic fibrosis in obese patients with NAFLD-Combined effects of oleoylethanolamide supplementation and calorie restriction: A triple-blind randomized controlled clinical trial.
Tutunchi, H, Ostadrahimi, A, Saghafi-Asl, M, Roshanravan, N, Shakeri-Bavil, A, Asghari-Jafarabadi, M, Farrin, N, Mobasseri, M
Journal of cellular physiology. 2021;(1):417-426
Abstract
Nonalcoholic fatty liver disease (NAFLD) is one of the most common noncommunicable diseases worldwide. The present study aimed to investigate the effects of oleoylethanolamide (OEA) supplementation combined with calorie restriction on inflammation, body composition, and hepatic fibrosis among obese patients with NAFLD. In this 12-week randomized clinical trial, 76 obese patients newly diagnosed with NAFLD were randomly allocated into either OEA or placebo group. The weight-loss diet was also designed for both groups. Pre- and postintervention messenger RNA expression levels of the transcription factor nuclear factor-κB (NF-κB), interleukin-6 (IL-6) and IL-10, body composition, and NAFLD fibrosis score were assessed. At the end of the study, the OEA group showed lower NF-κB and IL-6 expression levels compared to the placebo (p < .01). However, IL-10 expression level was approximately twofold higher in the OEA group compared to the placebo group (p = .008). A significant reduction was observed in the fat mass of the OEA group compared to the placebo (p = .044) postintervention. In addition, OEA supplementation led to a significant increase in fat-free mass in the OEA group compared to the placebo (p = .032). A remarkable increase was observed in resting metabolic rate (RMR) in the OEA group (p = .009); however, it was not found in the placebo group. There were no significant between-group differences in RMR postintervention. In addition, no significant within-and between-group differences were observed in the NAFLD fibrosis score at the end of the trial. Treatment with OEA along with weight-loss intervention could significantly improve inflammation and body composition in patients with NAFLD.
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Evaluation of Danzhi Xiaoyao powder and amlodipine sustained-release tablets in follow-up treatment of the hypertensive crisis and the interleukin-6 gene expression.
Wei, Q, Jing, Z, Zhi-Ye, H
Cellular and molecular biology (Noisy-le-Grand, France). 2021;(2):166-170
Abstract
Danzhi Xiaoyao powder (DXP) is an herbal formula with eight different herbs. This herbal medicine can play multiple roles in various disease treatments through its several components. In this study, the effect of DXP was evaluated on the treatment of hypertensive patients with and without amlodipine. For this purpose, 252 patients were studied with high blood pressure. The 126 patients received DXP, and the others received DXP + amlodipine for four weeks. Besides demographic and biochemical assessments (gender, BMI, age, SBP, DBP, etc.), the expression of the interleukin-6 gene was evaluated in these two groups. The results showed that the blood pressure decreased by DPX, and there was no significant difference in control of blood pressure by DPX and DXP + amlodipine. But it did not affect interleukin-6 gene expression. Therefore, it can be concluded that this drug probably uses a different mechanism than amlodipine to control blood pressure.
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The acute effect of incorporating lettuce or watercress into a moderately high-fat meal on postprandial lipid, glycemic response, and plasma inflammatory cytokines in healthy young men: a randomized crossover trial.
Shokraei, S, Khandouzi, N, Sina, Z, Nasrollahzadeh, J
Lipids in health and disease. 2021;(1):66
Abstract
BACKGROUND Postprandial responses to food mostly depend on the composition of the meal and the consumption of vegetables may modulate this postprandial state. In this study, the effects of lettuce or watercress consumption with a moderately high-fat meal (40% kcal from fat) on postprandial lipemia, glycemia, and inflammatory cytokines were determined in healthy men. METHODS This randomized, 3-arm, crossover study was conducted in sixteen healthy young men with a mean ± SEM age and body mass index (in kg/m2) of 22.8 ± 0.5 years old and 23.7 ± 1.16, respectively. Lettuce and watercress were added to the test meal in portions of 100 g and cellulose was added to the control meal. Thereafter, blood samples were collected by passing 0, 1, 2, 3, and 4 h for analysis. The postprandial response was measured in plasma glucose, triglycerides (TG), total cholesterol, high-density-lipoproteins cholesterol (HDL-C), and low-density-lipoproteins cholesterol (LDL-C), as the area under the postprandial curve (AUC). Moreover, plasma tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) were determined once before and once 4 h after the meal's consumption. RESULTS The 0-4-h AUCs for glucose (385.7, 361.9, and 382.3 mg/dL for the control, lettuce, and watercress meals, respectively) were calculated to be lower when meal was consumed with lettuce compared to the control (P < 0.05) and watercress (P < 0.01) meals. The maximum values of insulin were obtained as 43.8 ± 18.8, 33.5 ± 19.5, and 42.8 ± 17.7 μIU/mL for the control, lettuce, and watercress meals, respectively. As well, the lettuce-containing meal more reduced the AUC for insulin compared with the control (P < 0.05), but not watercress. Notably, plasma TG, total cholesterol, HDL-C, and LDL-C had no significant differences among the meals. Moreover, the levels of plasma IL-6 and TNF-α did not differ among the meals. CONCLUSION In this study on healthy men, the addition of lettuce to a moderately high-fat meal delayed the postprandial glycemic response. However, the effect of the consumption of these vegetables on postprandial responses in subjects with cardiometabolic risk factors remains to be elucidated yet. This clinical trial was registered at the Iran Clinical Trials Registration Office (IRCT) on March 3, 2018, with an ID of IRCT20160702028742N4 ( https://www.irct.ir/user/trial/23233/view ).
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Effects of long-term vitamin D and n-3 fatty acid supplementation on inflammatory and cardiac biomarkers in patients with type 2 diabetes: secondary analyses from a randomised controlled trial.
Limonte, CP, Zelnick, LR, Ruzinski, J, Hoofnagle, AN, Thadhani, R, Melamed, ML, Lee, IM, Buring, JE, Sesso, HD, Manson, JE, et al
Diabetologia. 2021;(2):437-447
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AIMS/HYPOTHESIS Interventions that reduce inflammation may delay progression of microvascular and macrovascular complications in diabetes. We examined the effects of vitamin D3 and/or n-3 fatty acid supplementation vs placebo on 5 year changes in serum inflammatory and cardiac biomarkers in adults with type 2 diabetes. METHODS This study reports pre-specified secondary outcomes of the Vitamin D and Omega-3 Trial to Prevent and Treat Diabetic Kidney Disease, in which 1312 US adults with type 2 diabetes and without known cardiovascular disease, malignancy, or end-stage kidney disease were randomised using computer-generated random numbers in blocks of eight to vitamin D3 (2000 IU/day) vs placebo and n-3 fatty acids (eicosapentaenoic acid [EPA] and docosahexaenoic acid [DHA]; 1 g/day) vs placebo in a 2 × 2 factorial design. Participants, examiners, and researchers assessing outcomes were blinded to intervention assignment. We measured serum IL-6, high-sensitivity C-reactive protein (hsCRP) and N-terminal pro-B-type natriuretic peptide (NT-proBNP) at baseline and after 2 and 5 years. RESULTS A total of 333 participants were randomised to vitamin D3 and placebo n-3 fatty acids, 289 to n-3 fatty acids and placebo vitamin D3, 370 to vitamin D3 and n-3 fatty acids, and 320 to 2 placebos; 989 (75%) and 934 (71%) participants returned blood samples at 2 and 5 years, respectively. Participants had a mean age of 67.6 years (46% women). Overall, baseline geometric means of IL-6, hsCRP and NT-proBNP were 1.2 pg/ml, 1.9 mg/l and 262 ng/l, respectively. After 5 years, mean IL-6 and hsCRP remained within 6% of their baseline values while mean NT-proBNP increased by 55% overall. Compared with placebo, participants assigned to vitamin D3 had a 1.24-fold greater increase in NT-proBNP over 5 years (95% CI 1.09, 1.41; p = 0.003), while IL-6 and hsCRP did not have a significant difference in change. Comparing n-3 fatty acids with placebo, there was no significant difference in change in IL-6, hsCRP or NT-proBNP. No heterogeneity was observed in subgroup analyses accounting for baseline eGFR, urine albumin to creatinine ratio, initial biomarker concentration, 25-hydroxyvitamin D level or EPA+DHA index. CONCLUSIONS/INTERPRETATION Among adults with type 2 diabetes, supplementation with vitamin D3 or n-3 fatty acids did not reduce IL-6, hsCRP or NT-proBNP over 5 years. TRIAL REGISTRATION ClinicalTrials.gov NCT01684722 FUNDING The study was funded by grant R01DK088762 from the National Institute of Diabetes and Digestive and Kidney Diseases. Graphical abstract.
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Multi-vitamin supplementation blunts the circulating IL-6/IL-10 ratio increase after knee arthroplasty: A randomized, double-blind, placebo controlled study.
Barker, T, Henriksen, VT, Rogers, VE, Trawick, RH, Momberger, NG, Lynn Rasmussen, G
Cytokine. 2021;:155435
Abstract
Circulating interleukin (IL)-6 and IL-10 concentrations can be elevated following the surgically induced trauma of total knee arthroplasty (TKA). An exaggerated increase in IL-6 relative to IL-10 (i.e., IL-6/IL-10 ratio) associates with trauma severity and indicative of pro-inflammatory predominance. Although various vitamins and minerals alter individual IL-6 and IL-10 concentrations in the blood, surprisingly, it is unknown if a multi-vitamin supplement alters the IL-6/IL-10 ratio during the systemic inflammatory response following TKA. The objective of this study was to identify if a multi-vitamin with mineral supplement taken prior to alters the circulating IL-6/IL-10 ratio following total knee arthroplasty (TKA). This study consisted of a randomized, double-blind, placebo controlled design. Twenty-one subjects undergoing elective, primary, unilateral TKA were randomly assigned to a placebo (PL, n = 11) or multi-vitamin with mineral supplement (MV, n = 10). Supplements were taken daily starting approximately 6-weeks prior to surgery. Supplements were not taken the day of surgery or during inpatient care 2-days after surgery. Circulating IL-6, IL-10, high-sensitivity CRP (hsCRP), vitamin C (ascorbic acid (AA)), vitamin D (25-hydroxyvitamin D (25(OH)D)), and vitamin E (α-tocopherol (αT)) concentrations were measured in fasting blood draw samples obtained ~6-weeks prior to surgery (and before starting supplementation), the morning of surgery, and 24-hours and 48-hours after surgery. MV supplementation tended to increase serum 25(OH)D and significantly increased plasma AA and plasma αT before surgery without mitigating the post-operative IL-6 and hsCRP increases. However, the post-operative increase in the serum IL-6/IL-10 ratio after surgery was significantly blunted in the MV group. Based on these findings, we conclude that a multi-vitamin with mineral supplement taken daily for several weeks before surgery might reduce the pro-inflammatory predominance after TKA. Future research confirming or refuting the novel data presented herein is needed.
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IL-6 inhibition with ziltivekimab in patients at high atherosclerotic risk (RESCUE): a double-blind, randomised, placebo-controlled, phase 2 trial.
Ridker, PM, Devalaraja, M, Baeres, FMM, Engelmann, MDM, Hovingh, GK, Ivkovic, M, Lo, L, Kling, D, Pergola, P, Raj, D, et al
Lancet (London, England). 2021;(10289):2060-2069
Abstract
BACKGROUND IL-6 has emerged as a pivotal factor in atherothrombosis. Yet, the safety and efficacy of IL-6 inhibition among individuals at high atherosclerotic risk but without a systemic inflammatory disorder is unknown. We therefore addressed whether ziltivekimab, a fully human monoclonal antibody directed against the IL-6 ligand, safely and effectively reduces biomarkers of inflammation and thrombosis among patients with high cardiovascular risk. We focused on individuals with elevated high-sensitivity CRP and chronic kidney disease, a group with substantial unmet clinical need in whom previous studies in inflammation inhibition have shown efficacy for cardiovascular event reduction. METHODS RESCUE is a randomised, double-blind, phase 2 trial done at 40 clinical sites in the USA. Inclusion criteria were age 18 years or older, moderate to severe chronic kidney disease, and high-sensitivity CRP of at least 2 mg/L. Participants were randomly allocated (1:1:1:1) to subcutaneous administration of placebo or ziltivekimab 7·5 mg, 15 mg, or 30 mg every 4 weeks up to 24 weeks. The primary outcome was percentage change from baseline in high-sensitivity CRP after 12 weeks of treatment with ziltivekimab compared with placebo, with additional biomarker and safety data collected over 24 weeks of treatment. Primary analyses were done in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of assigned treatment. The trial is registered with ClinicalTrials.gov, NCT03926117. FINDINGS Between June 17, 2019, and Jan 14, 2020, 264 participants were enrolled into the trial, of whom 66 were randomly assigned to each of the four treatment groups. At 12 weeks after randomisation, median high-sensitivity CRP levels were reduced by 77% for the 7·5 mg group, 88% for the 15 mg group, and 92% for the 30 mg group compared with 4% for the placebo group. As such, the median pairwise differences in percentage change in high-sensitivity CRP between the ziltivekimab and placebo groups, after aligning for strata, were -66·2% for the 7·5 mg group, -77·7% for the 15 mg group, and -87·8% for the 30 mg group (all p<0·0001). Effects were stable over the 24-week treatment period. Dose-dependent reductions were also observed for fibrinogen, serum amyloid A, haptoglobin, secretory phospholipase A2, and lipoprotein(a). Ziltivekimab was well tolerated, did not affect the total cholesterol to HDL cholesterol ratio, and there were no serious injection-site reactions, sustained grade 3 or 4 neutropenia or thrombocytopenia. INTERPRETATION Ziltivekimab markedly reduced biomarkers of inflammation and thrombosis relevant to atherosclerosis. On the basis of these data, a large-scale cardiovascular outcomes trial will investigate the effect of ziltivekimab in patients with chronic kidney disease, increased high-sensitivity CRP, and established cardiovascular disease. FUNDING Novo Nordisk.
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The impact of a randomized dietary and physical activity intervention on chronic inflammation among obese African-American women.
Babatunde, OA, Arp Adams, S, Truman, S, Sercy, E, Murphy, AE, Khan, S, Hurley, TG, Wirth, MD, Choi, SK, Johnson, H, et al
Women & health. 2020;(7):792-805
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Lifestyle interventions may reduce inflammation and lower breast cancer (BrCa) risk. This randomized trial assessed the impact of the Sistas Inspiring Sistas Through Activity and Support (SISTAS) study on plasma C-reactive protein (CRP), interleukin-6 (IL-6) and Dietary Inflammatory Index (DII). This unblinded, dietary and physical activity trial was implemented in 337 obese (body mass index [BMI] ≥30 kg/m2) African American (AA) women recruited between 2011 and 2015 in South Carolina through a community-based participatory approach with measurements at baseline, 3 months, and 12 months. Participants were randomized into either intervention (n = 176) or wait-list control group (n = 161). Linear mixed-effect models were used for analyses of CRP and IL-6. Baseline CRP was significantly higher in those with greater obesity, body fat percentage, and waist circumference (all p <.01). No difference was observed between groups for CRP or IL-6 at 3 or 12 months; however, improvements in diet were observed in the intervention group compared to the control group (p = .02) at 3 months but were not sustained at 12 months. Although the intervention was not successful at reducing levels of CRP or IL-6, a significant decrease was observed in DII score for the intervention group, indicating short-term positive dietary change.
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Caffeine supplementation induces higher IL-6 and IL-10 plasma levels in response to a treadmill exercise test.
Rodas, L, Martinez, S, Aguilo, A, Tauler, P
Journal of the International Society of Sports Nutrition. 2020;(1):47
Abstract
BACKGROUND An acute bout of exercise induces an inflammatory response characterized by increases in several cytokines. Caffeine ingestion could modify this inflammatory response. The aim of this study was to determine the effects of caffeine supplementation on plasma levels of cytokines, mainly IL-10 and IL-6, in response to exercise. METHODS In a randomized, crossover, double-blinded study design, thirteen healthy, well-trained recreational male athletes performed, on two different occasions, a treadmill exercise test (60 min at 70% VO2max) after ingesting 6 mg/kg body mass of caffeine or placebo. Blood samples were taken before exercising, immediately after finishing and 2 h after finishing the exercise. Plasma concentrations of IL-10, IL-6, IL-1β, IL-1ra, IL-4, IL-8, IL-12 and IFN-γ, adrenaline, cortisol and cyclic adenosine monophosphate (cAMP) were determined. The capacity of whole blood cultures to produce cytokines in response to endotoxin (LPS) was also determined. Changes in blood variables were analyzed using a time (pre-exercise, post-exercise, recovery) x condition (caffeine, placebo) within-between subjects ANOVA with repeated measures. RESULTS Caffeine supplementation induced higher adrenaline levels in the supplemented participants after exercise (257.3 ± 53.2 vs. 134.0 ± 25.7 pg·mL- 1, p = 0.03) and higher cortisol levels after recovery (46.4 ± 8.5 vs. 32.3 ± 5.6 pg·mL- 1, p = 0.007), but it did not influence plasma cAMP levels (p = 0.327). The exercise test induced significant increases in IL-10, IL-6, IL-1ra, IL-4, IL-8, IL-12 and IFN-γ plasma levels, with IL-6 and IL-10 levels remaining high after recovery. Caffeine supplementation influenced only IL-6 (3.04 ± 0.40 vs. 3.89 ± 0.62 pg·mL- 1, p = 0.003) and IL-10 (2.42 ± 0.54 vs. 3.47 ± 0.72 pg·mL- 1, p = 0.01) levels, with higher concentrations after exercise in the supplemented condition. No effect of caffeine was observed on the in vitro stimulated cytokine production. CONCLUSIONS The results of the present study indicate a significant influence of caffeine supplementation increasing the response to exercise of two essential cytokines such as IL-6 and IL-10. However, caffeine did not influence changes in the plasma levels of other cytokines measured and the in vitro-stimulated cytokine production.