Soluble Tumor Necrosis Factor Receptor Research Articles

Acute Kidney Injury, Systemic Inflammation and Long-term Cognitive Function: ASSESS-AKI.

Cognitive dysfunction is a well-known complication of chronic kidney disease, but it is less known whether cognitive decline occurs in survivors after acute kidney injury (AKI). We hypothesized that an episode of AKI is associated with poorer cognitive function, mediated, at least in part, by persistent systemic inflammation. ASSESS-AKI enrolled patients surviving three months after hospitalization with and without AKI matched based on demographics, comorbidities, and baseline kidney function. A subset underwent cognitive testing using the modified mini-mental status examination (3MS) at 3, 12, and 36 months. We examined the association of AKI with 3MS scores using mixed linear models and assessed the proportion of risk mediated by systemic inflammatory biomarkers. Among 1538 participants in ASSESS-AKI, 1420 (92%) completed the 3MS assessment at 3 months and had a corresponding matched participant. Participants with AKI had lower 3MS scores at three years (difference -1.1 (95% CI: -2.0, -0.3) P=0.009) compared to participants without AKI. A higher proportion of AKI participants had a clinically meaningful (≥ 5 point) reduction in 3MS scores at three years compared to participants without AKI (14% vs. 10%, P=0.04). In mediation analyses, plasma soluble tumor necrosis factor receptor-1 (sTNFR-1) at three months after AKI mediated 35% (P=0.02) of the AKI related risk for 3MS scores at three years. AKI was associated with lower 3MS scores and sTNFR-1 concentrations appeared to mediate a significant proportion of the risk of long-term cognitive impairment. Further work is needed to determine if AKI is causal or a marker for cognitive impairment.

Association of Baseline Serum Soluble Tumour Necrosis Factor Receptor Levels with the Response of Rheumatoid Arthritis to Janus Kinase Inhibitor Therapy.

The aim of this study was to investigate whether cytokines associated with tumour necrosis factor- (TNF-) α and interleukin- (IL-) 6 signalling could predict rheumatoid arthritis (RA) clinical remission (CR) with Janus kinase inhibitor (JAKinib) treatment using the Simplified Disease Activity Index (SDAI). Eighty-nine patients with RA treated with JAKinibs were enrolled, and their clinical data were collected retrospectively. CR was defined as an SDAI ≤ 3.3 after 6 months of treatment with JAKinib. The serum samples of 89 patients were analysed for IL-6, soluble IL-6 receptor (sIL-6R), soluble gp130 (spg130), and soluble TNF receptor- (sTNFR-) I and sTNFR-II titres. There were no significant differences in the baseline clinical parameters between the CR and non-CR groups. Serum levels of IL-6, sIL-6R, and sgp130 were not significantly different; whereas, the serum sTNFR-I and sTNFR-II levels were significantly lower in the CR group. Univariate and multivariate logistic regression analysis showed that the baseline log sTNFR II values (OR: 0.002; p = 0.034) were predictors of CR. Patients with RA can be stratified prior to JAKinib administration using serum sTNFR-I and sTNFR-II levels but not serum IL-6 axis cytokine levels (IL-6, sIL-6R, and sgp130).

Resistance training and cardiometabolic risk in women with metabolically healthy and unhealthy obesity.

Despite some reported benefits, there is a low quality of evidence for resistance training (RT) improving metabolic health of individuals with overweight or obesity. We evaluated the impact of RT on body composition, cardiorespiratory fitness (CRF) and physical performance, lipid-lipoprotein profile, inflammation, and glucose-insulin homeostasis in 51 postmenopausal women vs. 29 controls matched for age, obesity, and physical activity. Exercised women were further subdivided for comparison of RT effects into those presenting metabolically healthy obesity (MHO) and those with metabolically unhealthy obesity (MUHO) classified according to Karelis and Rabasa-Lhoret or an approach based on adipose tissue secretory dysfunction using the plasma adiponectin(A)/leptin (L) ratio. Participants followed a 4-month weekly RT program targeting major muscle groups (3x10 repetitions at 80% 1-RM). Percent fat marginally decreased and lean body mass increased (0.01<p<0.05) while CRF and muscular strength improved in all women, after RT (effect size [ES]: 0.11 to 1.21 [trivial to large effects], p˂0.01). Fasting plasma triacylglycerol and high-density lipoprotein-cholesterol levels slightly increased and decreased respectively in participants with MHO using the A/L ratio approach (ES: -0.47 to 1.07 [small to large effects], p˂0.05). Circulating interleukin-6 soluble receptor decreased in both groups and soluble tumor necrosis factor receptor-1/soluble tumor necrosis factor receptor-2 in women with MUHO only, irrespective of definition (ES: -0.42 to -0.84 [small to large effects], p˂0.05). Glucose-insulin homeostasis was unchanged regardless of group or definition. RT improved physical performance and body composition but had a lesser impact on cardiometabolic risk in women with obesity, irrespective of their metabolic phenotype.

Sesquiterpene Lactones Containing an α-Methylene-γ-Lactone Moiety Selectively Down-Regulate the Expression of Tumor Necrosis Factor Receptor 1 by Promoting Its Ectodomain Shedding in Human Lung Adenocarcinoma A549 Cells.

Alantolactone is a eudesmane-type sesquiterpene lactone containing an α-methylene-γ-lactone moiety. Previous studies showed that alantolactone inhibits the nuclear factor κB (NF-κB) signaling pathway by targeting the inhibitor of NF-κB (IκB) kinase. However, in the present study, we demonstrated that alantolactone selectively down-regulated the expression of tumor necrosis factor (TNF) receptor 1 (TNF-R1) in human lung adenocarcinoma A549 cells. Alantolactone did not affect the expression of three adaptor proteins recruited to TNF-R1. The down-regulation of TNF-R1 expression by alantolactone was suppressed by an inhibitor of TNF-α-converting enzyme. Alantolactone increased the soluble forms of TNF-R1 that were released into the culture medium as an ectodomain. The structure-activity relationship of eight eudesmane derivatives revealed that an α-methylene-γ-lactone moiety was needed to promote TNF-R1 ectodomain shedding. In addition, parthenolide and costunolide, two sesquiterpene lactones with an α-methylene-γ-lactone moiety, increased the amount of soluble TNF-R1. Therefore, the present results demonstrate that sesquiterpene lactones with an α-methylene-γ-lactone moiety can down-regulate the expression of TNF-R1 by promoting its ectodomain shedding in A549 cells.

Genetic factors associated with age-related macular degeneration modulating plasma inflammatory biomarker levels in patients with AIDS

ABSTRACT Introduction Patients with the acquired immunodeficiency syndrome (AIDS) have an increased prevalence and incidence of intermediate-stage age-related macular degeneration (AMD). Several elevated plasma inflammatory biomarkers are associated with increased incidence of intermediate-stage AMD in this population. We evaluated the association between AMD risk alleles and plasma inflammatory biomarker levels in persons with AIDS. Materials and Methods Cryopreserved plasma specimens of 229 non-Hispanic White and 252 non-Hispanic blacks from the Longitudinal Study of the Ocular Complications of AIDS cohort were assayed for plasma levels of soluble tumor necrosis factor receptor (sTNFR) 2, interleukin (IL)-18, C × 3motif chemokine ligand 1 (CX3CL1), C-reactive protein (CRP), and soluble CD14 (sCD14). Genotyping included AMD-associated variants rs10801553 and rs800292 for complement factor H (CFH) rs9332739 and rs547154 for complement factor 2 (C2), rs2230199 for C3, rs2285714 for CFI, and rs3732379 and rs3732378 for C × 3motif chemokine receptor 1 (CX3CR1). Results In Whites, AMD low-risk CX3CR1 variants (V249I and T280M) were associated with reduced plasma levels of IL-18. In Blacks, AMD low-risk C3 R102G and low-risk CX3CR1 T280M variants were associated with reduced CRP levels. Conclusions Genetic variants in AMD-associated immune genes may influence AMD-associated systemic plasma inflammatory biomarker levels in patients with AIDS.

Abstract 6300: Associations of biological aging with perceived stress in patients with head and neck cancer: A longitudinal study

Abstract Introduction: Biological aging leads to an increased risk of morbidity and mortality in patients with head and neck cancer (HNC) undergoing intensity-modulated radiotherapy (IMRT). This progression can be exacerbated by the burden of stress arising from HNC and IMRT. While stress has been linked to inflammation, the associations of biological aging measures including inflammatory markers and epigenetic age acceleration (EAA) with stress over cancer treatment remain underexplored. The purpose of this study was to examine the associations between biological aging and stress in patients with HNC receiving IMRT across four time points (i.e., pre- (T1), end of (T2), 3 months (T3), and 12 months (T4) post-IMRT). Methods: We conducted a prospective longitudinal study. Stress was assessed using the Perceived Stress Scale (PSS) across four time points along with the assessment of biological aging markers: peripheral inflammatory markers (i.e., interleukin [IL-6], IL-1β, IL-10, IL-1ra, C-reactive protein [CRP], soluble tumor necrosis factor receptor 2 [sTNFR2], and TNF-α) and EAA. EAA was calculated using DNAmPhenoAge, adjusted for chronological age. Liner mixed effects models were used to examine the associations between biological aging measures and stress across time. Results: A total of 176 patients with HNC were enrolled in the study with a mean age of 59.9±10.0 years, 72.7% male, and 77.3% non-Hispanic White. Stress scores increased from T1 to T2 (p&amp;lt;0.001), decreased significantly at T3 (p&amp;lt;0.001) which were lower than the baseline scores (T1), and then gradually decreased at T4 (p=0.029). Significant associations of CRP, IL- 1ra, and TNFR-2 with stress were identified across time (all p values &amp;lt;0.05), controlling for covariates (i.e., age, human papillomavirus status, chemotherapy, and surgery): elevated inflammatory markers were associated with higher levels of stress. In a separate model, higher stress scores were also associated with increased EAA controlling for the same covariates (p=0.015): an increment of 10 units in stress scores was associated with an age acceleration of 7.2 months across time. Conclusions: Findings from our study suggest that biological aging measures (inflammatory markers and EAA) are associated with stress across time in patients with HNC receiving IMRT. Clinicians and researchers may use the findings to develop personalized psychosocial interventions that reduce stress so as to deaccelerate biological aging for patients with HNC during their treatment and survivorship. Citation Format: Yufen Lin, Telisa Spikes, Deborah Bruner, Sudeshna Paul, Andrew Miller, Karen Conneely, Nabil Saba, Canhua Xiao. Associations of biological aging with perceived stress in patients with head and neck cancer: A longitudinal study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6300.

Therapeutic potential of procathepsin L-inhibiting and progesterone-entrapping dimethyl-β-cyclodextrin nanoparticles in treating experimental sepsis.

The pathogenic mechanisms of bacterial infections and resultant sepsis are partly attributed to dysregulated inflammatory responses sustained by some late-acting mediators including the procathepsin-L (pCTS-L). It was entirely unknown whether any compounds of the U.S. Drug Collection could suppress pCTS-L-induced inflammation, and pharmacologically be exploited into possible therapies. Here, we demonstrated that a macrophage cell-based screening of a U.S. Drug Collection of 1360 compounds resulted in the identification of progesterone (PRO) as an inhibitor of pCTS-L-mediated production of several chemokines [e.g., Epithelial Neutrophil-Activating Peptide (ENA-78), Monocyte Chemoattractant Protein-1 (MCP-1) or MCP-3] and cytokines [e.g., Interleukin-10 (IL-10) or Tumor Necrosis Factor (TNF)] in primary human peripheral blood mononuclear cells (PBMCs). In vivo, these PRO-entrapping 2,6-dimethal-β-cyclodextrin (DM-β-CD) nanoparticles (containing 1.35 mg/kg PRO and 14.65 mg/kg DM-β-CD) significantly increased animal survival in both male (from 30% to 70%, n = 20, P = 0.041) and female (from 50% to 80%, n = 30, P = 0.026) mice even when they were initially administered at 24h post the onset of sepsis. This protective effect was associated with a reduction of sepsis-triggered accumulation of three surrogate biomarkers [e.g., Granulocyte Colony Stimulating Factor (G-CSF) by 40%; Macrophage Inflammatory Protein-2 (MIP-2) by 45%; and Soluble Tumor Necrosis Factor Receptor I (sTNFRI) by 80%]. Surface Plasmon Resonance (SPR) analysis revealed a strong interaction between PRO and pCTS-L (KD = 78.2 ± 33.7 nM), which was paralleled with a positive correlation between serum PRO concentration and serum pCTS-L level (ρ = 0.56, P = 0.0009) or disease severity (Sequential Organ Failure Assessment, SOFA; ρ = 0.64, P = 0.0001) score in septic patients. Our observations support a promising opportunity to explore DM-β-CD nanoparticles entrapping lipophilic drugs as possible therapies for clinical sepsis.

Abstract B082: A pro-tumorigenic, aged microenvironment may aid in worsened disease progression in an HGSOC model

Abstract Over 70% of HGSOC patients are diagnosed after 55 and the average patient succumbs to disease at 70 years old. Despite this, most ovarian cancer research, and cancer studies generally, utilize young mice that are mimetic of human teenagers and/or do not investigate age as a variable despite it being the top cancer risk factor. An improved understanding of how age affects HGSOC progression may enable development of alternative treatment strategies aimed at intercepting metastasis and preventing cancer cells from establishing in the peritoneum. Our preliminary studies show tumor burden and disease severity are significantly higher in aged versus young animals. We developed an epithelial cell line derived from C57Bl/6 oviducts and used CRISPR-Cas9 genome editing to develop a syngeneic tumorigenic line harboring Trp53, Pten, and Brca2 deletions. After intraperitoneal injection into 6-week and 14-month-old immunocompetent C57Bl/6 mice, we observed a stark increase in tumor burden in aged mice. Furthermore, older mice died at a faster rate; all aged mice succumbed to disease within 1-month of inoculation compared to young mice surviving up to 3 months. Total RNA-sequencing of tumors harvested from aged and young mice is ongoing. Characterization of the tumor-naïve peritoneal compartment revealed the aged microenvironment to be highly inflammatory. When assessed via cytokine array, peritoneal fluid of aged mice had higher concentrations of inflammatory markers including soluble TNF receptor-1 (sTNFR-1), L-selectin, and VCAM-1. Flow cytometry of peritoneal lavage indicated an over 2-fold increase in the number CD45+ cells present in the peritoneal cavity, coinciding with cytokine array results. Within this population, there was nearly complete depletion of macrophage and neutrophil populations and a significant increase in B cells and CD4+ and CD8+ T cells. The percentage of PD-1+ CD8+ cells also increased. In addition to increased signs of inflammation, a significantly higher concentration of insulin-like growth factor-1 (IGF-I) and higher concentrations of the associated IGF binding proteins -3 and -6 were found in peritoneal fluid of aged mice. In addition, during tissue collection, organs of the aged mice were found to be much larger than young mice, a common effect of elevated IGF-I; aged omentum weighed 2-4 times that of young. Notably, IGF-I is known to inhibit apoptosis and promote proliferation and increased IGF-I is correlated with increased risk of breast, prostate, and lung cancer. A drastic difference in disease severity occurs when identical cancer cells are injected into 6-week and 14-month-old mice. To identify possible microenvironmental differences in the two populations, a broad panel of cytokines was assessed, and immune populations were quantified in pre-cancerous mice. Overall, multiple pro-inflammatory markers and the number of lymphocytes were upregulated in the aged peritoneal cavity, and markers of immune fatigue were present. Further work is aimed at identifying immune cell state via further cytometry and sequencing. Citation Format: Katherine A. Cummins, Ronny I. Drapkin, Matthew Knarr. A pro-tumorigenic, aged microenvironment may aid in worsened disease progression in an HGSOC model [abstract]. In: Proceedings of the AACR Special Conference on Ovarian Cancer; 2023 Oct 5-7; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_2):Abstract nr B082.

Soluble tumor necrosis factor receptor type 1 is an alternative marker of urinary albumin-creatinine ratio and estimated glomerular filtration rate for predicting the decline of renal function in subjects with type 2 diabetes mellitus

BackgroundUrinary albumin-creatinine ratio (UACR) and estimated glomerular filtration rates (eGFR) help predict worsening diabetic kidney disease (DKD) but have their limitations. Soluble tumor necrosis factor receptor type 1 (sTNFR1) is a biomarker of DKD. The predictive abilities of sTNFR1 and UACR plus eGFR have not been compared. MethodsThis prospective cohort study included patients with type 2 diabetes (T2D) to identify the risk factors of worsening DKD. Renal events were defined as > 30 % loss in eGFR based on consecutive tests after 6 months. The associations of sTNFR1, UACR, and eGFR levels and the risks of renal events were tested using a Cox regression model and the area under the curve (AUC) was compared between sTNFR1 levels and UACR plus eGFR using receiver-operating characteristic (ROC) analysis. The accuracy of stratification was evaluated using Kaplan–Meier analysis. ResultsLevels of sTNFR1 and UACR were associated with risks of > 30 % decline in eGFR after adjusting for relevant factors. The association between sTNFR1 levels and renal outcomes was independent of UACR and eGFR at baseline. The AUC of sTNFR1 level was comparable with that of combined UACR and eGFR (0.73 vs. 0.71, respectively, p = 0.72) and the results persisted for quartile groups of sTNFR1 and risk categories of Kidney Disease: Improving Global Outcomes (KDIGO) (0.70 vs. 0.71, respectively, p = 0.84). Both stratifications by sTNFR1 levels and KDIGO were accurate. ConclusionsTNFR1 could be an alternative marker for identifying patients with diabetes at risk of declining renal function.

Evidence supporting correlation between aging and dengue severity: A retrospective analysis on the 2010 dengue outbreak in Brazil

Objective: The aim of this study is to explore the role of aging and non-communicable diseases (NCDs) as potential risk factors for severe clinical manifestations of dengue. This investigation was conducted within a cohort of patients from the 2010 epidemic in Belo Horizonte, Brazil. Methods: A total of 144 subjects diagnosed with dengue were categorized into two groups, representing the early and late (critical) stages of the disease. Further stratification was performed based on age, distinguishing between young and aged subjects. NCD subjects were also divided into young and aged groups. The symptomatology, previous clinical history, age, and presence of NCDs were inquired. Blood samples were collected for the analysis of platelet, soluble tumor necrosis factor receptor 1 (sTNFR1), and aspartate aminotransferase (AST) levels. The Mann-Whitney test was explored for the comparison of two groups, whereas the Kruskal-Wallis test was used for the analysis of differences among the multiple groups. Categorical variables were examined by Chi-square test. Correlation assessments were conducted using binary logic regression analysis with a 95% confidence interval. P&lt;0.05 was considered statistically significant. Results: Compared to the younger subjects with NCDs, aged subjects exhibited a more severe form of dengue during the critical phase. The presence of NCDs was not associated with a worse dengue outcome in younger individuals, suggesting that aging itself maybe an important contributor to the severity of dengue. Conclusions: In the studied cohort, we emphasize that aging is a significant factor associated with severe manifestations of dengue. While we do not discard the potential role of NCDs in exacerbating disease progression, it may be more prominently impact the aged groups.

Comparison of Incidence or Recurrence of Anterior Uveitis in Patients with Ankylosing Spondylitis Treated with Tumor Necrosis Factor Inhibitors

Background: Anterior uveitis (AU) is a significant concern in patients with ankylosing spondylitis (AS), and the choice of tumor necrosis factor inhibitors (TNFi) as a treatment modality raises questions regarding its effects on AU. We compared the effects of TNFi on AU in patients with AS. Methods: Patients diagnosed with AS and treated with at least one TNFi, including anti-TNFα antibodies (adalimumab and infliximab) or a soluble TNF receptor molecule (etanercept), between January 2010 and December 2022, were retrospectively reviewed. We compared the recurrence rate of AU in patients with a history of uveitis and the incidence of new-onset AU in those without a history of uveitis among the three TNFi groups. We also compared the effects of two different TNFi agents in patients who underwent TNFi switching. Results: Within two years of treatment initiation, there was no significant difference in AU recurrence among the three TNFi groups. However, the incidence of new-onset AU was significantly higher in the etanercept group than in the adalimumab group (26.4% vs. 6.3%; p = 0.024). After two years, the AU recurrence rate was significantly lower in the adalimumab group than in the other groups (p &lt; 0.001). Among patients who underwent anti-TNFi switching, adalimumab treatment was associated with a significantly lower incidence of uveitis than etanercept (p = 0.023). Conclusion: In the short-term period following TNFi therapy, etanercept induced new-onset AU more frequently than adalimumab in patients with AS. Adalimumab recipients experienced fewer AU recurrences during the subsequent long-term period compared to other TNFi recipients.

The strong inverse association between plasma concentrations of soluble tumor necrosis factor receptors type 1 with adiponectin/leptin ratio in older women

Complex inflammatory crosstalk between muscular and adipose organs during ageing is controlled by adipokines and myokines. The Adiponectin/Leptin ratio (A/L ratio) has proven to be a promising biomarker for identifying insulin sensitivity, cardiovascular risk and adipose tissue inflammation. Although the A/L ratio has been related to inflammatory conditions, its ability to associate with or indicate the behavior of other inflammatory mediators remains unknown. The present study aimed to verify the association between the A/L ratio and a panel of inflammatory biomarkers in community-dwelling older women. The plasmatic concentrations of adiponectin, leptin, resistin, brain-derived neurotrophic factor (BDNF), interferon-gamma (IFN-γ), interleukins 2, 4, 5, 6, 8 and 10, tumour necrosis factor (TNF) and its soluble receptors (sTNF-r) 1 and 2 were evaluated in 71 community-dwelling older women with 75 (±7) years. The A/L ratio was negative and inverse correlated with BNDF (r = −0.29; p = 0.01), IL-8 (r = −0.37; p = 0.001) and sTNFr- 1 (r = −0.98; p < 0.001) levels. A strong and inverse association, with proportional effect, between A/L ratio and sTNFr-1 concentrations was found (Adjusted R2 = 0.22; β = −0.48; p > 0.001). It suggests that the presence of sTNFr-1 causes an inflammatory effect that affect cross-talk between muscle and adipose tissue, contributing to pro-inflammatory imbalance, which may have molecular and functional consequences. In addition, we provide insights into diagnostic biomarkers for inflammation, especially related to muscle wasting and intrinsic capacity in older people.

Correlation of Increased Soluble Tumor Necrosis Factor Receptor 1 with Mortality and Dependence on Treatment in Non-Small-Cell Lung Cancer Patients: A Longitudinal Cohort Study

Background: Tumor necrosis factor (TNF) is a multipotent cytokine involved in inflammation and anti-tumor activity. TNF-α exerts its function upon binding to TNF-receptor 1 (TNF-R1) and TNF-receptor 2 (TNF-R2). This study investigates the relationship of soluble (s) TNF-R1 levels in non-small-cell lung cancer (NSCLC) patients with treatment and overall survival. Methods: In total, 134 NSCLC patients treated at the Medical Faculty of Martin Luther University Halle-Wittenberg between 2017 and 2019 were included in this study. Serum levels of sTNF-R1 were measured via ELISA at baseline and during and after treatment. A linear mixed-effects model was used to assess sTNF-R1 changes over time. Linear regression was applied to investigate the association between clinical characteristics and changes in sTNF-R1. Cox regression models were used to estimate associations with overall mortality. Results: The estimated average sTNFR-1 at baseline was 2091.71 pg/mL, with a change of 6.19 pg/mL per day. Cox models revealed that the individual change in sTNF-R1 was more strongly associated with mortality than its baseline value, especially after adjusting for covariates. Conclusions: This study provides evidence that the individual change in sTNF-R1 levels during and after treatment were associated with the risk of mortality, suggesting the use of the sTNF-R1 trajectory as a prognostic marker.

Genetically engineered macrophages derived from iPSCs for self-regulating delivery of anti-inflammatory biologic drugs.

In rheumatoid arthritis, dysregulated cytokine signaling has been implicated as a primary factor in chronic inflammation. Many antirheumatic and biological therapies are used to suppress joint inflammation, but despite these advances, effectiveness is not universal, and delivery is often at high doses, which can predispose patients to significant off-target effects. During chronic inflammation, the inappropriate regulation of signaling factors by macrophages accelerates progression of disease by driving an imbalance of inflammatory cytokines, making macrophages an ideal cellular target. To develop a macrophage-based therapy to treat chronic inflammation, we engineered a novel induced pluripotent stem cell (iPSC)-derived macrophage capable of delivering soluble TNF receptor 1 (TNFR1), an anti-inflammatory biologic inhibitor of tumor necrosis factor alpha (TNF-α), in an auto-regulated manner in response to TNF-α. Murine iPSCs were differentiated into macrophages (iMACs) over a 17-day optimized protocol with continued successful differentiation confirmed at key timepoints. Varying inflammatory and immunomodulatory stimuli demonstrated traditional macrophage function and phenotypes. In response to TNF-α, therapeutic iMACs produced high levels of sTNFR1 in an autoregulated manner, which inhibited inflammatory signaling. This self-regulating iMAC system demonstrated the potential for macrophage-based drug delivery as a novel therapeutic approach for a variety of chronic inflammatory diseases.

Changes in Inflammatory Cytokines After Chronic Hepatitis C Treatment Among People Living With HIV.

We aimed to evaluate the effect of hepatitis C virus cure on serum inflammatory markers among people with HIV. Among 127 people with HIV, serum alanine aminotransferase, soluble tumor necrosis factor receptor 1, and inflammatory index score were significantly lower at the 24-week time point in patients who achieved sustained virologic response as compared with those who did not.

Effect of whole-body vibration stimulation on plasma soluble TNF receptors in elderly with sarcopenia: a randomized controlled trial.

Sarcopenia is a pathology resulting from a progressive and severe loss of muscle mass, strength, and function in the course of aging, which has deleterious consequences on quality of life. Among the most widespread studies on the issue are those focused on the effect of different types of physical exercise on patients with sarcopenia. This randomized controlled study aimed to compare the effects of a whole-body vibration exercise (WBV) session on the inflammatory parameters of non-sarcopenic (NSG, n=22) and sarcopenic elderly (SG, n=22). NSG and SG participants were randomly divided into two protocols: intervention (squat with WBV) and control (squat without WBV). After a one-week washout period, participants switched protocols, so that everyone performed both protocols. Body composition was assessed by dual-energy radiological absorptiometry (DXA) and function through the six-minute walk test (6MWD) and Short Physical Performance Battery (SPPB). Plasma soluble tumor necrosis factor receptors (sTNFR) were determined by enzyme-linked immunosorbent assay (ELISA) and measured before and immediately after each protocol. After exercise with WBV, there was an increase in sTNFR2 levels in the NSG (P<0.01; d=-0.69 (-1.30; -0.08) and SG (P<0.01, d=-0.95 (-1.57; -0.32) groups. In conclusion, an acute session of WBV influenced sTNFr2 levels, with sarcopenic individuals showing a greater effect. This suggested that WBV had a more pronounced impact on sTNFr2 in those with loss of muscle strength and/or physical performance. Additionally, WBV is gaining recognition as an efficient strategy for those with persistent health issues.

Deep phenotyping of dementia in a multi-ethnic cardiovascular cohort: The Multi-Ethnic Study of Atherosclerosis (MESA).

Our understanding of the specific aspects of vascular contributions to dementia remains unclear. We aim to identify the correlates of incident dementia in a multi-ethnic cardiovascular cohort. A total of 6806 participants with follow-up data for incident dementia were included. Probable dementia diagnoses were identified using hospitalization discharge diagnoses according to the International Classification of Diseases Codes (ICD). We used Random Forest analyses to identify the correlates of incident dementia and cognitive function from among 198 variables collected at the baseline MESA exam entailing demographic risk factors, medical history, anthropometry, lab biomarkers, electrocardiograms, cardiovascular magnetic resonance imaging, carotid ultrasonography, coronary artery calcium and liver fat content. Death and stroke were considered competing events. Over 14 years of follow-up, 326 dementia events were identified. Beyond age, the top correlates of dementia included coronary artery calcification, high sensitivity troponin, common carotid artery intima to media thickness, NT-proBNP, physical activity, pulse pressure, tumor necrosis factor-α, history of cancer, and liver to spleen attenuation ratio from computed tomography. Correlates of cognitive function included income and physical activity, body size, serum glucose, glomerular filtration rate, measures of carotid artery stiffness, alcohol use, and inflammation indexed as IL-2 and TNF soluble receptors and plasmin-antiplasmin complex. In a deeply phenotyped cardiovascular cohort we identified the key correlates of dementia beyond age as subclinical atherosclerosis and myocyte damage, vascular function, inflammation, physical activity, hepatic steatosis, and history of cancer.

Adalimumab Effectively Decreases Inflammation Downstream of TNFα Signaling in Synoviocytes from Extended Oligoarticular Juvenile Idiopathic Arthritis.

Fibroblast-like synoviocytes (FLS) play a critical role in inflammation that contributes to disease progression in juvenile idiopathic arthritis (JIA). In rheumatoid arthritis (RA), FLS express tumor necrosis factor alpha (TNFα). TNFα signaling has been shown to be upstream of transforming growth factor beta (TGFβ) signaling. Overexpression of TNFα and TGFβ, as well as related proteins, can cause increased inflammation in RA. In this study, we examine the effects of inhibiting TNFα signaling with adalimumab on FLS isolated from synovial fluid of patients with JIA. Synovial fluid samples were selected from 41 patients in our repository. Of these samples, 23 were diagnosed with persistent oligoarticular JIA and 18 were diagnosed with extended oligoarticular JIA. All samples were taken prior to patients extending to a polyarticular course, or what we termed extended-to-be (ETB), and were on no medications or nonsteroidal anti-inflammatory drugs (NSAIDs) only at the time of arthrocentesis. For cell studies, FLS were isolated from synovial fluid and treated with adalimumab for 24h. Protein antibody arrays were performed by RayBiotech, Inc. according to their protocols. In persistent FLS, TNFα (fold change [FC] = 1.2 p = 0.001), TGFβ (FC = 1.5 p = 0.001), lymphotoxin alpha (LTα) (FC = 4.3 p = 0.015), soluble tumor necrosis factor receptor1 (sTNFRI) (FC = 5.1 p = 0.008), and soluble tumor necrosis factor receptor2 (sTNFRII) (FC = 3.8 p = 0.025) were significantly elevated in adalimumab treated cells compared to untreated cells. In ETB FLS, TNFα was significantly elevated (FC = 1.04 p = 0.023) while TGFβ (FC = 1.03 p = 0.037) was significantly decreased in adalimumab-treated cells compared to untreated cells. This data suggests that, after only 24h, adalimumab is effective at decreasing inflammation that occurs downstream of initial TNFα signaling in extended-to-be fibroblast-like synoviocytes.

Endostatin, soluble tumour necrosis factor receptor 1 and soluble tumour necrosis factor receptor 2 cannot predict new onset of microalbuminuria in patients with type 2 diabetes.

Inflammation and angiogenesis play an important role in the development of early diabetic kidney disease. We investigated the association of soluble Tumour Necrosis Factor Receptor 1 (sTNF-R1), sTNF-R2 and endostatin with new onset microalbuminuria in normoalbuminuric patients with diabetes mellitus type 2. We conducted a case control study to assess serum levels of sTNF-R1, sTNF-R2 and endostatin in 169 patients with new onset microalbuminuria and in 188 matched normoalbuminuric, diabetic controls. Baseline serum samples from participants of the ROADMAP (Randomized Olmesartan and Diabetes Microalbuminuria Prevention) and observational follow-up (ROADMAP-OFU) studies were used. Endostatin and sTNF-R1 but not sTNF-R2 were increased at baseline in patients with future microalbuminuria. In the multivariate analysis, each log2 increment in endostatin levels was associated with an increase of only 6% in the risk of development of microalbuminuria (adjusted HR (95% CI) 1.006 (1.001-1011). sTNF-R1 and sTNF-R2 levels were conversely associated with microalbuminuria, but the results did not reach statistical significance. The respective adjusted HRs (95% CI) were 1.305 (0.928-1.774) and 0.874 (0.711-1.074). sTNF-R1 and sTNF-R2 failed to predict the occurrence of microalbuminuria in normoalbuminuric patients with type 2 diabetes. Likewise, the utility of endostatin in predicting new onset proteinuria is limited.

Association between biomarkers of redox status and cytokines with different patterns of habitual physical activity in eutrophic and overweight/obese preschoolers: multivariate analysis of a cross-sectional study

BackgroundAlthough it is well known that obesity is frequently associated with reduced levels of habitual physical activity (HPA), which contributes to determining severe oxidative stress and inflammatory state, this association is however unknown in preschoolers so far. This study aimed to investigate the association between biomarkers of redox status and cytokines with different patterns of HPA according to the adiposity of preschoolers.MethodsA cross-sectional study was conducted in 50 preschoolers (25 overweight/obese, OW/OB and 25 eutrophic, EU), matched for age, sex, economic level, and maternal education. Total antioxidant capacity (TAC), superoxide dismutase (SOD) and catalase (CAT) activities, substances reactive to thiobarbituric acid (TBARS), soluble tumor necrosis factor receptors (sTNFRs), and leptin levels were evaluated. HPA levels were evaluated by accelerometry (ActiGraph GT9X accelerometer). Correlation, multiple linear regression, and partial least squares regression analysis were used to determine the association between redox status biomarkers and cytokines with different patterns of HPA (HPA level, bouts of moderate to vigorous physical activity [MVPA], and multivariate pattern of HPA) in EU and OW/OB preschoolers.ResultsOW/OB preschoolers had lower CAT activity, higher levels of TAC, TBARS, and cytokines, and similar levels of HPA to EU preschoolers. In EU preschoolers, SOD activity exhibited a stronger negative association with moderate intensity ranges of HPA (R2 = 0.18), and negative correlation with sTNFRs (r = -0.40 to -0.46). TBARS had a stronger positive association with ranges of light intensity in the multivariate pattern of HPA (R2 = 0.10). In OW/OB preschoolers, the HPA multivariate associative pattern was predominantly from vigorous intensity ranges. Thus, SOD activity had a positive association with the multivariate pattern of HPA (R2 = 0.38) and MVPA bouts (β [95% CI] = 0.457 [0.0026. 0.0576]). TAC had a negative association with the multivariate pattern of HPA (R2 = 0.38) and MVPA bouts (β [95% CI] = -0.718 [-0.0025. -0.0003]). Additionally, leptin levels were lower in OW/OB preschoolers engaged in vigorous physical activity (VPA) (8000–9999 counts/min) for longer periods of time.ConclusionThe results of this study indicate that OW/OB preschoolers have higher levels of oxidative stress biomarkers and pro-inflammatory cytokines compared to EU preschoolers. Moreover, VPA may exert antioxidative and anti-inflammatory effects in OW/OB preschoolers.