Soluble Tumor Necrosis Factor Receptor Research Articles

Changes in anthropometry, adiposity, and inflammation in Black and White women engaged in intentional weight loss.

We examined associations among changes in anthropometry, regional adiposity, and inflammatory markers in Black and White women participating in intentional weight loss. A total of 104 women with BMI ≥ 25 kg/m2 self-selected bariatric surgery (n = 66) or a diet and exercise program (n = 38). Anthropometric, dual-energy x-ray absorptiometry-quantified regional adiposity, and inflammatory markers (C-reactive protein [CRP], tumor necrosis factor α [TNF-α], soluble TNF receptor I [sTNFRI], sTNFRII, interleukin [IL]-6, and soluble IL-1 receptor antagonist) were measured at baseline and 6 months. Weight, BMI, visceral adipose tissue, and regional (android and gynoid) adiposity declined in the bariatric surgery group. Among bariatric surgery participants, Black women experienced declines of lesser magnitude in terms of weight and BMI than White women, but changes in regional adiposity and visceral adipose tissue did not differ. In the bariatric surgery group, decreases in weight and BMI were associated with decreases in CRP and IL-6 among White women, but not Black women. Decreases in weight, BMI, and android fat were associated with increases in TNF-α, sTNFRI, and sTNFRII among Black women, but not White women. Decreases in anthropometry and adiposity were observed among Black and White bariatric surgery participants; however, associations among changes in adiposity, anthropometry, and inflammation differed by race.

Role of baseline soluble tumor necrosis factor receptor 2 as a biomarker in primary podocytopathy: Implications for renal impairment and disease progression

BackgroundPodocytopathies, including minimal change disease (MCD), focal segmental glomerulosclerosis (FSGS), and collapsing glomerulopathy (CG), are kidney diseases that damage glomerular podocytes, leading to heavy proteinuria and nephrotic syndrome (NS). Inflammation plays a critical role in the progression of chronic kidney disease (CKD), with recent studies linking inflammatory biomarkers to declining kidney function. Tumor necrosis factor-alpha (TNF-α), an essential inflammatory cytokine, interacts with its circulating receptors, TNFR1 and TNFR2. The TNF-α pathway has been implicated in the pathogenesis of FSGS and MCD. Increased circulating TNFR2 levels have been associated with worsening renal function in podocytopathies, suggesting that the TNF-α inflammatory pathway significantly contributes to disease progression.MethodsWe conducted a study involving 53 patients with biopsy-proven MCD or FSGS and 53 healthy, age- and gender-matched controls. All patients were followed for 18 months. We analyzed serum and urine TNFR2 levels and gene expression at baseline and after three months. To assess the ability of TNFR2 to predict persistent decline in estimated glomerular filtration rate (eGFR < 30 mL/min/1.73m2), remission, and relapse, we employed Cox regression analysis. Additionally, we evaluated its prognostic utility for predicting progression to stage 4 CKD using ROC curve analysis.ResultsSerum and urine TNFR2 levels were significantly elevated in patients compared to controls. Serum TNFR2 was a significant predictor in univariate Cox regression analysis for persistent eGFR decline (HR 1.017, 95% CI: 1.003 to 1.032, p = 0.018), remission (HR 0.995, 95% CI: 0.992 to 0.999, p = 0.006), and relapse (HR 1.005, 95% CI: 1.001 to 1.010, p = 0.029). The ROC curve analysis demonstrated that serum TNFR2 levels had a strong prognostic ability for predicting progression to stage 4 CKD, with an AUC of 0.848 (95% CI: 0.737—0.960), sensitivity of 81%, and specificity of 71%.ConclusionThis study underscores the critical role of circulating TNFR2 in kidney injury among patients with primary podocytopathy. Elevated TNFR2 levels are significant predictors of persistent eGFR decline and disease relapse, highlighting their potential as biomarkers for disease progression and prognosis.

Individuals Who Had a Lifetime History of Suicide Attempts and Their Relationships With Inflammation, Severity of Depressive Symptoms, and Childhood Maltreatments

Abstract Lifetime history of suicide attempts is associated with inflammatory mechanisms, severity of depressive symptoms, and childhood trauma. This cross-sectional study enrolled 54 suicide attempters and 154 nonsuicide attempters. All individuals were assessed through a questionnaire, a structured clinical interview, scales, anthropometric measures, and laboratory biomarkers. Individuals with a history of lifetime suicide attempts showed significant positive correlations regarding soluble tumor necrosis factor receptor 1 and severity of depressive symptoms (p = 0.013), interleukin-1 receptor antagonist and severity of depressive symptoms (p = 0.04), and absenteeism from work and childhood physical abuse (p = 0.012). Suicide attempters also experienced more childhood trauma (sexual abuse, physical abuse, emotional abuse, emotional neglect, and physical neglect) compared with nonsuicide attempters. IL-4 levels were significantly lower in individuals who attempted suicide than in nonsuicidal individuals. Lifetime suicide attempts in major affective disorders were associated with childhood trauma and proinflammatory and anti-inflammatory cytokines.

Host Response Markers of Inflammation and Endothelial Activation Associated with COVID-19 Severity and Mortality: A GeoSentinel Prospective Observational Cohort

Background: The effect of the COVID-19 pandemic on healthcare systems emphasized the need for rapid and effective triage tools to identify patients at risk of severe or fatal infection. Measuring host response markers of inflammation and endothelial activation at clinical presentation may help to inform appropriate triage and care practices in patients with SARS-CoV-2 infection. Methods: We enrolled patients with COVID-19 across five GeoSentinel clinical sites (in Italy, Belgium, Canada, and the United States) from September 2020 to December 2021, and analyzed the association of plasma markers, including soluble urokinase-type plasminogen activator receptor (suPAR), soluble tumor necrosis factor receptor-1 (sTREM-1), interleukin-6 (IL-6), interleukin-8 (IL-8), complement component C5a (C5a), von Willebrand factor (VWF-a2), and interleukin-1 receptor antagonist (IL-1Ra), with 28-day (D28) mortality and 7-day (D7) severity (discharged, hospitalized on ward, or died/admitted to the ICU). Results: Of 193 patients, 8.9% (16 of 180) died by D28. Higher concentrations of suPAR were associated with increased odds of mortality at D28 and severity at D7 in univariable and multivariable regression models. The biomarkers sTREM-1 and IL-1Ra showed bivariate associations with mortality at D28 and severity at D7. IL-6, VWF, C5a, and IL-8 were not as indicative of progression to severe disease or death. Conclusions: Our findings confirm previous studies’ assertions that point-of-care tests for suPAR and sTREM-1 could facilitate the triage of patients with SARS-CoV-2 infection, which may help guide hospital resource allocation.

Regulation of plasma soluble receptors of TNF and IL-1 in patients with COVID-19 differs from that observed in sepsis

IL-1α/β and TNF are closely linked to the pathology of severe COVID-19 and sepsis. The soluble forms of their receptors, functioning as decoy receptors, exhibit inhibitory effects. However, little is known about their regulation in severe bacterial and viral infections, which we aimed to investigate in this study. The circulating soluble receptors of TNF (sTNFR1 and sTNFR2) and IL-1α/β (sIL-1R1, sIL-1R2) were evaluated in the plasma of patients with COVID-19, severe bacterial infections, and sepsis and compared with healthy controls. Additionally, IL1R1, IL1R2, TNFRSF1A, and TNFRSF1B expression was evaluated at the single cell level in PBMCs derived from COVID-19 or sepsis patients. Plasma concentrations of sIL-1R1, sTNFR1, and sTNFR2 were significantly higher in COVID-19 patients compared to healthy subjects. Notably, sIL-1R1 levels were particularly elevated in ICU COVID-19 patients, and transcriptome analysis indicated heightened IL1R1 expression in PBMCs from severe COVID-19 patients. In severe bacterial infections, only sTNFR1 and sTNFR2 exhibited increased levels compared to healthy controls. Sepsis patients had decreased sIL-1R1 plasma concentrations but elevated sIL-1R2, sTNFR1, and sTNFR2 levels compared to healthy individuals, reflecting the heightened expression due to the increased numbers of monocytes present in sepsis. Finally, elevated concentrations of sIL-1R2, sTNFR1, and sTNFR2 were moderately associated with reduced 28-day survival in sepsis patients. Our study reveals distinct regulation of plasma concentrations of soluble IL-1 receptors in COVID-19 and sepsis. Moreover, soluble TNF receptors 1 and 2 consistently rise in all conditions and show a positive correlation with disease severity in sepsis.

Transition from acute kidney injury to chronic kidney disease: mechanisms, models, and biomarkers.

Acute kidney injury (AKI) and chronic kidney disease (CKD) are increasingly recognized as interconnected conditions with overlapping pathophysiological mechanisms. This review examines the transition from AKI to CKD, focusing on the molecular mechanisms, animal models, and biomarkers essential for understanding and managing this progression. AKI often progresses to CKD due to maladaptive repair processes, persistent inflammation, and fibrosis, with both conditions sharing common pathways involving cell death, inflammation, and extracellular matrix (ECM) deposition. Current animal models, including ischemia-reperfusion injury (IRI) and nephrotoxic damage, help elucidate these mechanisms but have limitations in replicating the complexity of human disease. Emerging biomarkers such as kidney injury molecule-1 (KIM-1), neutrophil gelatinase-associated lipocalin (NGAL), and soluble tumor necrosis factor receptors (TNFRs) show promise in early detection and monitoring of disease progression. This review highlights the need for improved animal models and biomarker validation to better mimic human disease and enhance clinical translation. Advancing our understanding of the AKI-to-CKD transition through targeted therapies and refined research approaches holds the potential to significantly improve patient outcomes.

A randomized proof-of-mechanism trial of TNF antagonism for motivational deficits and related corticostriatal circuitry in depressed patients with high inflammation.

Chronic, low-grade inflammation has been associated with motivational deficits in patients with major depression (MD). In turn, impaired motivation has been linked to poor quality of life across psychiatric disorders. We thus determined effects of the anti-inflammatory drug infliximab-a potent tumor necrosis factor (TNF) antagonist-on behavioral and neural measures of motivation in 42 medically stable, unmedicated MD patients with a C-reactive protein >3 mg/L. All patients underwent a double-blind, placebo-controlled, single-dose, randomized clinical trial with infliximab (5 mg/kg) versus placebo. Behavioral performance on an effort-based decision-making task, self-report questionnaires, and neural responses during event-related functional magnetic resonance imaging were assessed at baseline and 2 weeks following infusion. We found that relative to placebo, patients receiving infliximab were more willing to expend effort for rewards. Moreover, increase in effortful choices was associated with reduced TNF signaling as indexed by decreased soluble TNF receptor type 2 (sTNFR2). Changes in effort-based decision-making and sTNFR2 were also associated with changes in task-related activity in a network of brain areas, including dorsomedial prefrontal cortex (dmPFC), ventral striatum, and putamen, as well as the functional connectivity between these regions. Changes in sTNFR2 also mediated the relationships between drug condition and behavioral and neuroimaging measures. Finally, changes in self-reported anhedonia symptoms and effort-discounting behavior were associated with greater responses of an independently validated whole-brain predictive model (aka "neural signature") sensitive to monetary rewards. Taken together, these data support the use of anti-inflammatory treatment to improve effort-based decision-making and associated brain circuitry in depressed patients with high inflammation.

The effects of the MTHFR 677C>T (rs1801133) genetic variant on susceptibility and disability worsening in multiple sclerosis patients are mediated by homocysteine

BackgroundInteractions between genetic and environmental variables contribute to the autoimmune inflammatory process in multiple sclerosis (MS). Elevated homocysteine levels, and vitamin D, vitamin B12, and folate deficiencies are some of the environmental factors associated with the pathogenesis of MS. Considering that the relationship between MTHFR 677C>T (rs1801133) genetic variant, homocysteine, and folate in patients with MS remains unclear and that their role were not extensively explored in the clinical course of the disease, we investigated whether this variant and plasma homocysteine and folate levels are associated with MS susceptibility, disability, disability progression, and inflammatory biomarkers. MethodsThe case-control study included 163 patients with MS categorized using the Expanded Disability Status Scale (EDSS) as mild (EDSS<3) and moderate/high (EDSS≥3) disability, and 226 healthy controls (HC). Disability progression was evaluated using Multiple Sclerosis Severity Score (MSSS) and the MTHFR 677C>T variant was genotyped using real time polymerase chain reaction. The plasma levels of some inflammatory biomarkers were determined. Two new composed scores were proposed: the first, namely as inflammatory activity index (IAI), was entered as a latent vector extracted from the macrophage M1 + T helper (Th)1 + Th17 + Th2 + T regulatory (Treg) cytokines, + tumor necrosis factor (TNF)-α+ soluble TNF receptor (sTNFR)-1 + sTNFR2. The second score, namely MS-severity index was entered as a latent vector extracted from the EDSS + MSSS scores + MS diagnosis. ResultsPatients with MS showed higher homocysteine and folate than controls (p < 0.001); homocysteine, and the M1, Th1, Th17, and Th2 Treg cytokine values were different between the three study groups and increased from HC to MS patients with mild disability and to MS patients with moderate/high disability (p < 0.0001). The levels of TNF-α and their soluble receptors sTNFR1 and sTNFR2 were higher in MS patients with EDSS≥3 than in the two other groups (EDSS<3 and HC) (p < 0.001). There was no association between the MTHFR 677 C > T genotypes and MS susceptibility, disability and disability progression (p > 0.05). Moreover, 21.8 % of the disability variance was explained by age, IAI and C-reactive protein (CRP) (all positively associated); 10.9 % of the disability progression variance was predicted by IAI and CRP (both positively) and 25-hydroxyvitamin D (negatively), whereas 54.4 % of the severity index (MS-EDSS-MSSS) was explained by the regression on age, IAI, homocysteine, folate, and CRP (all positively), and adiponectin, body mass index, and 25-hydroxyvitamin D (all negatively), female sex, and the MTHFR 677 TT genotype. In patients and controls, 16.6 % of the variance in the homocysteine was explained by the MTHFR 677 TT genotype and age (both positively), folate (negatively) and male sex. ConclusionThe MTHFR 677C>T variant has an indirect effect on the increase in disability in patients with MS, which also depends on factors such as age, sex, ad folate status.

Associations between circulating levels of FABP4 and TNF receptors are more evident in patients with type 2 diabetes mellitus than in patients with type 1 diabetes mellitus.

Fatty acid-binding protein 4 (FABP4) is an adipokine that plays significant roles in the development of insulin resistance and atherosclerosis. High levels of soluble tumor necrosis factor receptors (TNFRs) including TNFR1 and TNFR2 are associated with renal dysfunction and increased mortality in patients with diabetes mellitus (DM). However, the association between circulating levels of FABP4 and TNFRs remains unclear. We investigated the associations of FABP4 with TNFRs and metabolic markers in Japanese patients with type 1 DM (T1DM, n = 76, men/women: 31/45) and type 2 DM (T2DM, n = 575, men/women: 312/263). FABP4 concentration was positively correlated with levels of TNFR1 and TNFR2 in both patients with T1DM and those with T2DM. Multivariable regression analyses showed that there were independent associations of FABP4 concentration with body mass index (BMI) and estimated glomerular filtration rate (eGFR) after adjustment for age and sex in both patients with T1DM and those with T2DM. FABP4 concentration was independently associated with circulating levels of TNFR1 and TNFR2 after adjustment for the confounders in patients with T2DM but not in those with T1DM. Similarly, levels of TNFR1 and TNFR2 were independently associated with FABP4 concentration after adjustment for age, sex, systolic blood pressure, duration of DM and levels of eGFR, high-density lipoprotein cholesterol, and C-reactive protein in patients with T2DM but not in those with T1DM. FABP4 concentration is independently associated with levels of TNFRs in patients with DM, but the association is more evident in patients with T2DM than in those with T1DM.

Inflammation: Is It a Healer, Confounder, or a Promoter of Cardiometabolic Risks?

Inflammation is the body's non-specific response to injury or infection. It is a natural defense mechanism that helps to maintain homeostasis and promotes tissue repair. However, excessive inflammation can lead to cellular, tissue, or organ dysfunction, as well as contribute to the development of acute vascular events and diseases like Crohn's disease, psoriasis, obesity, diabetes, and cancer. The initial response to injury involves the activation of platelets and coagulation mechanisms to stop bleeding. This is followed by the recruitment of immune cells and the release of cytokines to promote tissue repair. Over time, the injured tissue undergoes remodeling and returns to its pre-injury state. Inflammation is characterized by the activation of inflammatory signaling pathways involving cytokines, chemokines, and growth factors. Mast cells play a role in initiating inflammatory responses. Pattern recognition receptors (PRRs) such as Toll-like receptors (TLRs) and nucleotide-binding domain (NOD)-like receptors (NLRs) are involved in the activation of these inflammatory pathways. Inflammasomes, which are cytoplasmic complexes, also contribute to inflammation by activating cytokines. Inflammation can also be triggered by factors like dietary components and the composition of the gut microbiota. Dysregulation of the gut microbiome can lead to excessive inflammation and contribute to diseases like atherosclerosis and irritable bowel syndrome (IBS). The immune system and gut-associated lymphoid tissue (GALT) play crucial roles in the inflammatory response and the development of conditions like colorectal cancer. Anti-inflammatory therapy can play a significant role in reducing or inducing the remission of inflammatory diseases such as Crohn's disease and ulcerative colitis. The fetal origin of adult diseases theory suggests that conditions during fetal development, such as low birth weight and maternal obesity, can influence the risk of cardiometabolic diseases later in life. All of the known risk factors associated with cardiometabolic diseases such as hypertension, excess weight, obesity, type-2 diabetes, and vascular diseases are accompanied by chronic low-grade inflammation. Inflammation seems to have a role in precipitating even acute vascular events such as heart attacks and stroke. Common markers of inflammation associated with cardiometabolic disease include interleukin (IL)-1β, IL-6, tumor necrosis factor (TNF-α), C-reactive protein (CRP), and soluble TNF receptors such as sTNFR1 and sTNFR2. These markers serve as indicators of systemic inflammation. However, these markers are not disease-specific but provide an insight into the overall chronic inflammatory status. In fact, inflammation has been identified as a potential target for future treatments to reduce or reverse the risk of atherosclerosis-related complications. The regulation of inflammation is complex, and further research is needed to better understand its mechanisms and develop strategies for managing inflammatory disorders. In summary, inflammation is a natural response to injury or infection, but excessive or prolonged inflammation can lead to the progression of various diseases. Understanding the underlying mechanisms of inflammation is important for developing treatments and preventive measures for inflammatory disorders.

Decoy receptors as biomarkers for exploring aetiology and designing new therapies.

Soluble decoy receptors (DR) are circulating proteins that act as molecular traps for ligands that modulate various signalling pathways. These proteins can be exploited as biomarkers and, in some cases, as drugs in various disease contexts. Inflammation is a key area where DRs have shown significant potential. By binding to pro-inflammatory cytokines, inflammatory DRs, such as soluble tumour necrosis factor receptors (sTNFRs), can inhibit downstream inflammatory signalling. This modulation of the inflammatory response holds promise for therapeutic interventions in various inflammatory conditions, including cardiovascular and chronic kidney diseases. Soluble DRs for advanced glycation end products (sRAGE) bind to advanced glycation end products (AGEs), reducing their detrimental effects on vascular function and atherosclerosis. High circulating sRAGE levels are associated with a lower risk for CV events, highlighting the potential of these soluble receptors for assessing the role of AGEs in CV diseases and managing the attendant risk. DRs may serve as biomarkers and therapeutic agents to advance our understanding of disease mechanisms and improve patients' outcomes. Their ability to modulate signalling pathways in a controlled manner opens up new opportunities for therapeutic interventions in various diseases, ranging from inflammation to cardiovascular and renal disorders.

Molecular Phenotyping of Patients with Sepsis and Kidney Injury and Differential Response to Fluid Resuscitation.

Previous work has identified two AKI sub-phenotypes (SP1 and SP2) characterized by differences in inflammation and endothelial dysfunction. Here we identify these sub-phenotypes using biospecimens collected in the emergency department and test for differential response to restrictive versus liberal fluid strategy in sepsis-induced hypotension in the CLOVERS trial. We applied a previously validated 3-biomarker model using plasma angiopietin-1 and 2, and soluble tumor necrosis factor receptor-1 to classify sub-phenotypes in patients with kidney dysfunction (AKI or end-stage kidney disease [ESKD]). We also compared a de novo latent class analysis (LCA) to the 3-biomarker based sub-phenotypes. Kaplan-Meier estimates were used to test for differences in outcomes and sub-phenotype by treatment interaction. Among 1289 patients, 846 had kidney dysfunction on enrollment and the 3-variable prediction model identified 605 as SP1 and 241 as SP2. The optimal LCA model identified two sub-phenotypes with high correlation with the 3-biomarker model (Cohen's Kappa 0.8). The risk of 28 and 90-day mortality was greater in SP2 relative to SP1 independent of AKI stage and SOFA scores. Patients with SP2, characterized by more severe endothelial injury and inflammation, had a reduction in 28-day mortality with a restrictive fluid strategy versus a liberal fluid strategy (26% vs 41%), while patients with SP1 had no difference in 28-day mortality (10% vs 11%) (p-value-for-interaction = 0.03). Sub-phenotypes can be identified in the emergency department that respond differently to fluid strategy in sepsis. Identification of these sub-phenotypes could inform a precision-guided therapeutic approach for patients with sepsis-induced hypotension and kidney injury.

Exercise: Just What the Doctor Ordered, But Why? Elucidating Mechanisms for Women's Increased High-Density Lipoprotein Benefit From Exercise and for the Health ABC Study.

High-density lipoprotein (HDL) is protective against cardiovascular disease. Exercise can increase HDL concentration, and some evidence suggests that this effect occurs more strongly in women than in men. Both HDL and exercise are associated with inflammation. We hypothesized a sex-by-exercise interaction on HDL level, whereby women would benefit from exercise more strongly than men, and tumor necrosis factor alpha and serum soluble tumor necrosis factor receptor-2 would mediate this relationship. This study included 2,957 older adult participants (1,520 women; 41% Black, 59% White; 73.6-years-old) from the Health, Aging, and Body Composition study. Regression models revealed a positive exercise-HDL relationship in women only (sex-by-exercise interaction: β = 0.09, p = .013; exercise on HDL in women: β = 0.07, p = .015), mediated by TNFα (axb = 0.15; CI: 0.01, 0.30), suggesting that exercise may increase HDL levels in women through reduced inflammation. Given that vascular risk contributes to Alzheimer's disease risk, findings have implications for sex differences in AD risk factors.

#1358 The association between TNFRSF1B rs1061624 polymorphism and hypertension in end-stage kidney disease patients on dialysis

Abstract Background and Aims In chronic kidney disease (CKD), hypertension (HT) is commonly found during its development and is a leading cause for its progression. HT, dyslipidemia and visceral obesity are among the components of metabolic syndrome (MetS) and seem to associate with progression of CKD to end-stage kidney disease (ESKD). Enhanced levels of soluble tumor necrosis factor receptor 2 (sTNFR2) are known to associate with progressive CKD; and this biomarker was reported as an independent predictor of all-cause mortality in ESKD patients under dialysis. Concerning the TNFRSF1B gene, the polymorphism rs1061624 (A &amp;gt; G), located in the 3′-untranslated region (3′-UTR), was associated with the development of HT in men and with increased risk of MetS. The aim of this study was to determine the genotype frequencies of TNFRSF1B rs1061624 in ESKD patients with and without HT, and to evaluate its relationship with the circulating levels of some MetS biomarkers. Method We studied 277 ESKD patients on dialysis (recruited between 2016-2019), 170 diagnosed with HT and 107 without HT (no-HT group); age, sex, body mass index (BMI), systolic blood pressure (SBP), diastolic blood pressure (DBP) and statin therapy were recorded. Real time PCR TaqMan SNP genotyping assay was used to assess genotype frequencies of TNFRSF1B rs1061624. We also evaluated the conventional lipid profile and the levels of oxidized low-density lipoprotein, adiponectin and leptin. Results The genotype frequencies in patients with and without HT were different (P = 0.002); the AA genotype was less frequent in HT than in no-HT group, while GG and AG genotypes were more frequent. Considering the AA genotype carriers, HT ESKD patients (n = 23), compared to the no-HT group (n = 33), presented lower adiponectin levels (P = 0.025); for the AG genotype carriers, HT group (n = 89) presented a trend towards lower adiponectin concentrations (P = 0.055), and were younger than no-HT patients (n = 48; P&amp;lt;0.001); in both comparisons, groups were matched for sex, BMI and number of patients under statins treatment, and in the first case also for age. Considering GG genotype, HT patients (n = 58) only differed from no-HT subjects (n = 26) in SBP, that was higher (P&amp;lt;0.001). Among HT patients, AG genotype carriers presented higher DBP (P = 0.004), lower values of leptin (P = 0.012) and leptin/adiponectin ratio (P = 0.022) and were younger (P&amp;lt;0.001) than GG genotype patients; compared to AA carriers, cholesterol levels were lower (P = 0.012). For the no-HT group, AG genotype patients presented lower DBP (P = 0.008) than AA genotype carriers. Conclusion The genotype frequencies were different in ESKD patients with and without HT, being G allele more frequent in HT. The HT ESKD patients with the AA or the AG genotypes seem to present lower adiponectin levels than the ESKD no-HT patients with the same genotypes. Acknowledgements This work was financed by CESPU, through the project SNPsCKD-GI2-CESPU-2022; FCT, in the scope of the project UIDP/04378/2020 and UIDB/04378/2020 of the Research Unit on Applied Molecular Biosciences—UCIBIO and the project LA/P/0140/2020 of the Associate Laboratory Institute for Health and Bioeconomy—i4HB.

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.

Spinal TNF-α receptor expression in a rodent model of respiratory motor neuron death

Intrapleural injection of cholera toxin B fragment conjugated to saporin (CTB-SAP) selectively kills respiratory motor neurons, and mimics aspects of neurodegenerative diseases including breathing deficits. In this model, phrenic long-term facilitation (pLTF) induced by acute intermittent hypoxia is enhanced following 7 days (d) of CTB-SAP vs. control rats, whereas pLTF in 28d CTB-SAP treated rats is comparable to pLTF in controls suggesting that the underlying mechanisms of plasticity at both time points differ. Inflammation is a hallmark of neurodegenerative diseases and is known to prevent pLTF. Furthermore, ketoprofen (NSAID) delivery attenuates pLTF in 7d CTB-SAP-treated rats, but enhances it in 28d CTB-SAP-treated rats; this suggests that inflammation contributes to pLTF in 7d CTB-SAP-treated rats, but undermines pLTF in 28d CTB-SAP-treated rats. In addition, cervical spinal inflammatory marker gene expression ( e.g., TNF-a) is increased in CTB-SAP rats, and pilot data suggest that soluble TNF receptor 1 (sTNFR1) inhibition differentially affects pLTF (Nichols and Smith , ibid). Thus, the goal of the current study is to investigate TNFR1 as a pharmacological target that can modulate inflammation to maximize pLTF and breathing in CTB-SAP rats. We hypothesized that C4 TNFR1 expression would be increased on phrenic motor neurons and glial cells of CTB-SAP rats vs. controls. To address this, we studied TNFR1 expression on phrenic motor neurons and glial cells using immunohistochemistry, confocal microscopy, and ImageJ analysis in male Sprague Dawley rats 7 and 28 days after intrapleural injection of: CTB-SAP or un-conjugated CTB and SAP (control); n=8/group. Our preliminary data (n=4/group) suggest that phrenic TNFR1 expression is increased in 7d CTB-SAP rats vs. controls (p&lt;0.05), but is unaffected in 28d CTB-SAP rats vs. controls (p&gt;0.05). Further data analysis is underway for phrenic as well as glial TNFR1 expression in CTB-SAP rats vs. controls. If C4 TNFR1 expression is increased, this would suggest that TNFR1 is a viable target for therapeutic intervention in CTB-SAP rats, and potentially in patients with breathing deficits due to respiratory motor neuron death. NSF Computational Neuroscience grant, MU CVM COR grant, and Spinal Cord Injury &amp; Disease Research Program grant. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

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 versus 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 (3 × 10 repetitions at 80% one repetition maximum (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): 0.11-1.21 (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.

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.