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Modulation of Cardiometabolic Disease Markers by Type I Interferon Inhibition in Systemic Lupus Erythematosus.
Casey, KA, Smith, MA, Sinibaldi, D, Seto, NL, Playford, MP, Wang, X, Carlucci, PM, Wang, L, Illei, G, Yu, B, et al
Arthritis & rheumatology (Hoboken, N.J.). 2021;(3):459-471
Abstract
OBJECTIVE Neutrophil dysregulation and the type I interferon (IFN) axis have been proposed to contribute to premature cardiovascular disease, a leading cause of mortality in patients with systemic lupus erythematosus (SLE). In the present study, we evaluated the ability of anifrolumab, a type I IFN receptor-blocking antibody, to reduce neutrophil extracellular trap (NET) formation and modulate cardiometabolic disease markers in comparison to placebo. METHODS Study subjects comprised patients with moderate-to-severe SLE who were enrolled in phase IIb of the MUSE trial (A Phase II, Randomized Study to Evaluate the Efficacy and Safety of MEDI-546 in Subjects with Systemic Lupus Erythematosus), with healthy individuals as controls. Blood samples were collected from SLE patients (n = 305) and healthy controls (n = 10-20) before the initiation of treatment (baseline) and from SLE patients after they had been treated with 300 mg of anifrolumab (n = 99) or placebo (n = 102). Baseline IFN gene signature test status was determined, and the IFN gene signature (21-gene panel) was monitored over time. Serum proteins were measured by multiplex immunoassay or ultrasensitive Simoa assay. NET complexes, cholesterol efflux capacity (CEC), and glycoprotein acetylation (GlycA) and other lipid parameters were assessed in plasma. RESULTS Formation of NET complexes and levels of tumor necrosis factor (TNF) and interleukin-10 (IL-10) were correlated with extent of type I IFN pathway activity. NET complexes and IL-10 levels were up-regulated in SLE patients compared to healthy controls (P < 0.008). The cardiometabolic disease markers CEC and GlycA were also found to be dysregulated in patients with SLE (P < 0.001 versus healthy controls). Type I IFN receptor inhibition with anifrolumab significantly reduced NET complexes and GlycA and improved CEC compared to baseline (P < 0.05) whereas no improvements were seen with placebo. Levels of TNF and IL-10 were reduced with anifrolumab compared to placebo (P < 0.05). CONCLUSION These data support a key role for type I IFNs in modulating factors contributing to SLE vasculopathy and suggest that inhibition of this pathway could decrease cardiovascular risk in individuals with SLE.
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The effect of glutamine supplementation on serum levels of some inflammatory factors, oxidative stress, and appetite in COVID-19 patients: a case-control study.
Mohajeri, M, Horriatkhah, E, Mohajery, R
Inflammopharmacology. 2021;(6):1769-1776
Abstract
BACKGROUND Malnutrition is seen in COVID-19 patients, and reducing malnutrition with appropriate therapies may improve these patients' health. This case-control study aimed to assess and compare serum levels of some inflammatory factors, oxidative stress, and appetite in COVID-19 patients with respiratory infections that receive glutamine treatment with a control group. METHODS In this study, patients who consented to use glutamine were considered as the case group and other patients who did not use glutamine were considered as a control group. Two hundred twenty-two COVID-19 patients (51.2 ± 6.7) using L-Glutamine and 230 COVID-19 patients (51.3 ± 8.2) with similar age, gender, and clinical status, as the control group, were included in the study. For 5 days, the case group consumed 10 g of glutamine supplement three times per day. At the end of the 5 days, blood samples were taken again to test for serum levels of IL1β, tumor necrosis factor-α, malondialdehyde, and total antioxidant capacity, then all data were analyzed. RESULTS Serum levels of β-1 interleukin, tumor necrosis factor-α and hs-CRP were significantly reduced with five days of glutamine supplementation (p < 0.05), and patients' appetite during 5 days of glutamine supplementation compared with the control group had a significant increase (p < 0.05). CONCLUSION Glutamine supplementation in COVID-19 patients with respiratory infection significantly reduces serum levels of interleukin-1 β, hs-CRP, and tumor necrosis factor-α and significantly increases appetite, so glutamine supplementation may be useful for COVID-19 patients in the hospital.
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TNFα Mediates the Interaction of Telomeres and Mitochondria Induced by Hyperglycemia: A Rural Community-Based Cross-Sectional Study.
Lyu, L, He, S, Zhang, H, Li, W, Zeng, J, Ping, F, Li, YX
Oxidative medicine and cellular longevity. 2020;:8235873
Abstract
This study is aimed at evaluating the relationship between leukocyte telomere length (LTL) and mitochondrial DNA copy number (mtDNAcn) in a noninterventional rural community of China with different glucose tolerance statuses. In addition, we investigate whether the indicators of oxidative stress and inflammation were involved and identify mediators among them. A total of 450 subjects in rural China were included and divided into two groups according to a 75 g oral glucose tolerance test (OGTT): the abnormal glucose metabolism (AGM, n = 257, 57.1%) group and the normal glucose tolerance (NGT, n = 193, 42.9%) group. Indicators of oxidative stress (superoxide dismutase (SOD) and glutathione reductase (GR)) and inflammatory indices (tumor necrosis factor α (TNFα) and interleukin-6 (IL-6)) were all determined by ELISA. LTL and mtDNAcn were measured using a real-time PCR assay. Linear regressions were used to adjust for covariates that might affect the relationship between LTL and mtDNAcn. Mediation analyses were utilized to evaluate the mediators. In the AGM, LTL was correlated with mtDNAcn (r = 0.214, p = 0.001), but no correlation was found in the NGT. The association between LTL and mtDNAcn was weakened after adjusting for inflammatory factors in the AGM (p = 0.087). LTL and mtDNAcn were both inversely related to HbA1c, IL-6, TNFα, and SOD activity. Mediation analysis demonstrated that TNFα was a significant mediator in the telomere-mitochondrial interactome in the AGM. This result suggests that inflammation and oxidative stress may play a vital role in telomere shortening as well as mitochondrial dysfunction. In the subjects with hyperglycemia, a significant positive correlation is observed between LTL and mtDNAcn, which is probably mediated by TNFα. TNFα may be considered a potential therapeutic target against aging-related disease in hyperglycemia.
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Gene expression of thrombomodulin, TNF-α and NF-KB in coronary artery disease patients of Pakistan.
Rafiq, M, Liaquat, A, Saeed, N, Shamshad, GU, Mumtaz, S, Khan, MJ
Molecular biology reports. 2020;(10):7575-7582
Abstract
Thrombomodulin (THBD) is an endothelial surface glycoprotein receptor, having a pivotal role in maintaining laminar blood flow. It functions to protect endothelial integrity by exhibiting anti-coagulation and anti-inflammatory properties thereby playing a key role in cardiovascular disease (CVD) pathology. Cholesterol lowering drugs have shown to alter the anti-inflammatory effects of cytokines. Understanding the molecular aspects of THBD gene and its relation to inflammatory cytokines is important to identify new prognostic and therapeutic targets for the CVD treatments. The present study was conducted to measure the expression of THBD, TNF-α and NF-kB genes in coronary artery disease patients (CAD) in Pakistani population. Lipid profile and BMI was compared both on fifty CAD patients and fifty healthy individuals. Expression analysis for THBD, TNF-α and NF-kB was carried out using real time PCR. The effect of lipid lowering drugs on cardiometabolic risk variables especially gene expression was analyzed. Our results indicated that the difference in BMI was marginal; however LDL-cholesterol and triglycerides levels in CAD patients were significantly higher than healthy individuals. THBD gene was significantly up-regulated whereas TNF-α and NF-kB were significantly down regulated in CAD individuals. Further exploration revealed that these variations were accounted to the use of statins by the patients. The use of statins by CAD patients up-regulated the mRNA expression of THBD by down-regulation of inflammatory mediators. The enhanced expression of endothelial THBD in response to cholesterol lowering drugs establishes a novel pleiotropic target that can be of clinical significance in thromboembolic and inflammatory disorders.
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The Value of Total antioxidant Status and Serum Tumor Necrosis Factor-α Levels at 24-28 Weeks of Gestation in the Prediction of Optimal Treatment Protocol in Gestational Diabetes Mellitus.
Ozler, S, Oztas, E, Uygur, D, Ersoy, AO, Ergin, M, Koca, C, Danisman, N, Erkaya, S
Experimental and clinical endocrinology & diabetes : official journal, German Society of Endocrinology [and] German Diabetes Association. 2019;(7):485-491
Abstract
AIM: The aim of this study was to investigate the serum oxidative stress markers, antioxidant enzyme and tumor necrosis factor-α (TNF-α) levels at 24-28 weeks of gestation and to evaluate the predictive value of them on the subsequent treatment protocol in gestational diabetes mellitus (GDM). METHODS A total of 58 GDM patients (30 treated with only conventional healthy dietary recommendation (CHDR), 28 treated with insulin) and 30 healthy pregnant women at 24-28 weeks of gestation, were enrolled in this prospective case-control study. The oxidative status, antioxidant enzyme and TNF-α levels were evaluated to determine if there is an association with the need of insulin therapy for glycemic control by using multivariable logistic regression analysis. RESULTS TNF-α (OR=11.976, 95%CI: 2.441-58.754, P=0.002) and total antioxidant status (TAS) (OR=12.769, 95%CI: 2.464-66.182, P=0.002) were found to be predictive for GDM at 24-28 weeks of gestation. Besides, further evaluation considering the treatment modality showed that increased TNF-α (OR=18.615, 95%CI: 2.338-148.240, P=0.006) and lower TAS levels (OR=99.471, 95%CI: 2.865-3 453.061, P=0.011) were independent predictors of the need for insulin treatment in GDM patients. CONCLUSIONS Increased TNF-α levels and low TAS are significantly associated with the increased risk of insulin requirement for achieving good glycemic control in GDM.
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Plasma leptin, but not resistin, TNF-α and adiponectin, is associated with echocardiographic parameters of cardiac remodeling in patients with coronary artery disease.
Farcaş, AD, Rusu, A, Stoia, MA, Vida-Simiti, LA
Cytokine. 2018;:46-49
Abstract
The aim of this research was to assess the relationship between plasma adiponectin, leptin, resistin, tumor necrosis factor alpha (TNF-α) levels and echocardiographic parameters of ventricular remodeling in patients with coronary artery disease, without acute myocardial infarction. The study population consisted of 49 patients with echocardiographic measurements performed. After adjustment for age, gender, body mass index, systolic and diastolic blood pressure, and glycaemia, adiponectin was statistically significant associated with interventricular septum thickness (β = -0.304), left ventricular posterior wall thickness (β = -0.402), left ventricular end diastolic diameter (LVEDD; β = 0.385) and left ventricular relative wall thickness (β = -0.448, p < .05 for all). The associations were no longer significant when only patients without diabetes were included in the analysis. Leptin was associated with LVEDD (β = -0.354) and left ventricular relative wall thickness (β = 0.385, p < .05 for all). No associations between resistin, TNF-α and echocardiographic left ventricular parameters assessed were found in these patients. In conclusion, in patients with coronary artery disease and without acute myocardial infarction leptin may represent a potential mechanism of adverse cardiac remodeling. Resistin and TNF-α might not be involved in ventricular remodeling in these patients.
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Growth Improvement with Adalimumab Treatment in Children with Moderately to Severely Active Crohn's Disease.
Walters, TD, Faubion, WA, Griffiths, AM, Baldassano, RN, Escher, J, Ruemmele, FM, Hyams, JS, Lazar, A, Eichner, S, Huang, B, et al
Inflammatory bowel diseases. 2017;(6):967-975
Abstract
BACKGROUND Growth failure is common in children with Crohn's disease. The effect of adalimumab (ADA), a fully human antitumor necrosis factor antagonist, on height velocity in pediatric patients with baseline (BL) linear growth impairment in the IMAgINE 1 trial is presented. METHODS This analysis included female and male patients with growth potential (bone age ≤13 and ≤14 yr, respectively), with BL Pediatric Crohn's disease Activity Index >30, and who failed or were intolerant to conventional therapy. Patients received open-label induction ADA at weeks 0 and 2 by body weight (≥40 kg, 160 and 80 mg and <40 kg, 80 and 40 mg). At week 4, patients were randomized to double-blind high (40 or 20 mg for ≥40 kg or <40 kg) or low dose (20 or 10 mg for ≥40 kg or <40 kg) every other week ADA to week 52. Height velocity z-score was summarized at BL, week 26, and week 52 by patients with BL growth impairment (z-score ≤-1.0) or normal growth (z-score >-1.0). RESULTS ADA therapy significantly improved and normalized growth rate at weeks 26 and 52 in patients with BL growth impairment (median z-score, BL, -3.25; week 26, -0.34; and week 52, 0.21; P < 0.001 versus BL for both), but not in patients with normal growth. Growth improvement was significantly greater at week 26 in week 4 responders to induction therapy compared with nonresponders (median z-score 0.09 versus -2.92; P = 0.02). CONCLUSIONS ADA treatment resulted in growth rate normalization as early as week 26 in children with moderately to severely active Crohn's disease and growth impairment.
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Factors Associated with Higher Pro-Inflammatory Tumor Necrosis Factor-α Levels in Young Women with Type 1 Diabetes.
Danielson, KK, Monson, RS, LeCaire, TJ
Experimental and clinical endocrinology & diabetes : official journal, German Society of Endocrinology [and] German Diabetes Association. 2016;(3):140-7
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Abstract
AIMS: While cytokines play a role in the etiology of type 1 diabetes, cytokines later in the disease are less understood. We therefore investigated associations of pro-inflammatory tumor necrosis factor-α levels measured at prolonged disease duration with C-peptide at diagnosis, long-term glycemic control, diabetes duration, clinical factors, and health behaviors. METHODS Data and blood were collected during an ancillary study to the longitudinal Wisconsin Diabetes Registry, a population-based cohort followed since diagnosis of type 1 diabetes. The ancillary study was conducted at 13-18 years diabetes duration, and enrolled premenopausal women age 18-45 years (n=87). RESULTS Higher tumor necrosis factor-α levels at 13-18 years diabetes duration were independently associated with longer duration (p=0.0004) and worse current renal function (p=0.02). Additionally, diabetes duration modified both of the positive associations of tumor necrosis factor-α levels (both interactions p≤0.01) with mean glycemic control during the previous 10 years (significant only in women with longer durations) and current daily caffeine intake (significant only in women with shorter durations). In women with C-peptide measured at diagnosis (n=50), higher tumor necrosis factor-α levels at 13-18 years duration were associated with lower C-peptide (p=0.01), independent of glycemic control during the previous 10 years. CONCLUSIONS Lower residual C-peptide at diagnosis and poor long-term glycemic control independently predicted higher pro-inflammatory tumor necrosis factor-α levels years later. The novel relationship with C-peptide needs confirmation in a larger cohort. Given the association between tumor necrosis factor-α and diabetes complications, further longitudinal studies may help clarify the potentially complex associations between glycemic control, inflammatory cytokines, and complications.
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LC-MS metabolomics of psoriasis patients reveals disease severity-dependent increases in circulating amino acids that are ameliorated by anti-TNFα treatment.
Kamleh, MA, Snowden, SG, Grapov, D, Blackburn, GJ, Watson, DG, Xu, N, Ståhle, M, Wheelock, CE
Journal of proteome research. 2015;(1):557-66
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Abstract
Psoriasis is an immune-mediated highly heterogeneous skin disease in which genetic as well as environmental factors play important roles. In spite of the local manifestations of the disease, psoriasis may progress to affect organs deeper than the skin. These effects are documented by epidemiological studies, but they are not yet mechanistically understood. In order to provide insight into the systemic effects of psoriasis, we performed a nontargeted high-resolution LC-MS metabolomics analysis to measure plasma metabolites from individuals with mild or severe psoriasis as well as healthy controls. Additionally, the effects of the anti-TNFα drug Etanercept on metabolic profiles were investigated in patients with severe psoriasis. Our analyses identified significant psoriasis-associated perturbations in three metabolic pathways: (1) arginine and proline, (2) glycine, serine and threonine, and (3) alanine, aspartate, and glutamate. Etanercept treatment reversed the majority of psoriasis-associated trends in circulating metabolites, shifting the metabolic phenotypes of severe psoriasis toward that of healthy controls. Circulating metabolite levels pre- and post-Etanercept treatment correlated with psoriasis area and severity index (PASI) clinical scoring (R(2) = 0.80; p < 0.0001). Although the responsible mechanism(s) are unclear, these results suggest that psoriasis severity-associated metabolic perturbations may stem from increased demand for collagen synthesis and keratinocyte hyperproliferation or potentially the incidence of cachexia. Data suggest that levels of circulating amino acids are useful for monitoring both the severity of disease as well as therapeutic response to anti-TNFα treatment.
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Plasma TNF-α and Soluble TNF Receptor Levels after Doxorubicin with or without Co-Administration of Mesna-A Randomized, Cross-Over Clinical Study.
Hayslip, J, Dressler, EV, Weiss, H, Taylor, TJ, Chambers, M, Noel, T, Miriyala, S, Keeney, JT, Ren, X, Sultana, R, et al
PloS one. 2015;(4):e0124988
Abstract
PURPOSE Chemotherapy-induced cognitive impairment (CICI) is a common sequelae of cancer therapy. Recent preclinical observations have suggested that CICI can be mediated by chemotherapy-induced plasma protein oxidation, which triggers TNF-α mediated CNS damage. This study evaluated sodium-2-mercaptoethane sulfonate (Mesna) co-administration with doxorubicin to reduce doxorubicin-induced plasma protein oxidation and resultant cascade of TNF-α, soluble TNF receptor levels and related cytokines. METHODS Thirty-two evaluable patients were randomized using a crossover design to receive mesna or saline in either the first or second cycle of doxorubicin in the context of a standard chemotherapy regimen for either non-Hodgkin lymphoma or breast cancer. Mesna (360 mg/m2) or saline administration occurred 15 minutes prior and three hours post doxorubicin. Pre-treatment and post-treatment measurements of oxidative stress, TNF-α and related cytokines were evaluated during the two experimental cycles of chemotherapy. RESULTS Co-administration of mesna with chemotherapy reduced post-treatment levels of TNF-related cytokines and TNF-receptor 1 (TNFR1) and TNF-receptor 2 (TNFR2) (p = 0.05 and p = 0.002, respectively). Patients with the highest pre-treatment levels of each cytokine and its receptors were the most likely to benefit from mesna co-administration. CONCLUSIONS The extracellular anti-oxidant mesna, when co-administered during a single cycle of doxorubicin, reduced levels of TNF-α and its receptors after that cycle of therapy, demonstrating for the first time a clinical interaction between mesna and doxorubicin, drugs often coincidentally co-administered in multi-agent regimens. These findings support further investigation to determine whether rationally-timed mesna co-administration with redox active chemotherapy may prevent or reduce the cascade of events that lead to CICI. TRIAL REGISTRATION clinicaltrials.gov NCT01205503.