Circulating Tumor Necrosis Factor Research Articles

Albuminuria and Serum Tumor Necrosis Factor Receptor Levels in Patients with Type2 Diabetes on SGLT2 Inhibitors: A Prospective Study.

Large-scale clinical trials of sodium-glucose cotransporter2 inhibitors (SGLT2i) demonstrate proteinuria-reducing effects in diabetic kidney disease, even after treatment with renin-angiotensin inhibitors. The precise mechanism for this favorable effect remains unclear. This prospective open-label single-arm study investigated factors associated with a reduction in proteinuria after SGLT2i administration. Patients with type2 diabetes (T2DM) who had glycated hemoglobin (HbA1c) levels ≥ 6.5% despite dietary and/or oral hypoglycemic monotherapy were recruited and administered the recommended daily dose of SGLT2i for 4months. Dual primary outcomes were changes in the urine albumin-to-creatinine ratio (uACR) and urine liver-type fatty acid-binding protein (L-FABP)-to-creatinine ratio (uL-FABPCR) at month4 from baseline. Changes in kidney injury, inflammation, and oxidative stress biomarkers were investigated as secondary endpoints to examine the effects of this treatment on the kidney. The correlation between renal outcomes and clinical indicators, including circulating tumor necrosis factor receptors (TNFR) 1 and 2, was evaluated using univariate and multivariate analyses. Participants (n = 123) had a mean age of 64.1years (SD 13.4), with 50.4% being male. The median BMI was 25.8 kg/m2 (interquartile range (IQR) 23.1-28.9), and the median HbA1c level was 7.3% (IQR 6.9-8.3). After SGLT2i administration, the uACR declined from 19.2mg/gCr (IQR 7.1-48.7) to 13.3mg/gCr (IQR 7.5-31.6), whereas the uL-FABPCR was not influenced. In univariate analysis, the change in log-transformed uACR due to SGLT2i administration showed a positive correlation with the change in serum TNFR1 level (R = 0.244, p < 0.01). Multivariate regression analysis, including confounding factors, showed that the changes in serum TNFR1 level were independently associated with the changes in the log-transformed uACR (independent t = 2.102,p < 0.05). After the 4-month SGLT2i administration, decreased albuminuria level was associated with decreased serum TNFR level in patients with T2DM. UMIN000031947.

Divergent tumor and immune cell reprogramming underlying immunotherapy response and immune-related adverse events in lung squamous cell carcinoma

BackgroundLung squamous cell carcinoma (LUSC) remains a leading cause of cancer-related deaths with few therapeutic strategies. Immune checkpoint inhibitors (ICIs) have demonstrated promising efficacy in patients with LUSC. However, ICIs...

Acute Kidney Injury-Induced Circulating TNFR1/2 Elevations Correlate with Persistent Kidney Injury and Progression to Fibrosis.

Elevated levels of circulating tumor necrosis factor receptors 1 and 2 (cTNFR1/2) predict chronic kidney disease (CKD) progression; however, the mechanisms of their release remain unknown. Whether acute kidney injury (AKI) drives cTNFR1/2 elevations and whether they predict disease outcomes after AKI remain unknown. In this study, we used AKI patient serum and urine samples, mouse models of kidney injury (ischemic, obstructive, and toxic), and progression to fibrosis, nephrectomy, and related single-cell RNA-sequencing datasets to experimentally test the role of kidney injury on cTNFR1/2 levels. We show that TNFR1/2 serum and urine levels are highly elevated in all of the mouse models of kidney injury tested, beginning within one hour post injury, and correlate with its severity. Consistent with this, serum and urine TNFR1/2 levels are increased in AKI patients and correlate with the severity of kidney failure. Kidney tissue expression of TNFR1/2 after AKI is only slightly increased and bilateral nephrectomies lead to strong cTNFR1/2 elevations, suggesting the release of these receptors by extrarenal sources. The injection of the uremic toxin indoxyl sulfate in healthy mice induces moderate cTNFR1/2 elevations. Moreover, TNF neutralization does not affect early cTNFR1/2 elevations after AKI. These data suggest that cTNFR1/2 levels in AKI do not reflect injury-induced TNF activity, but rather a rapid response to loss of kidney function and uremia. In contrast to traditional disease biomarkers, such as serum creatinine or BUN, cTNFR1/2 levels remain elevated for weeks after severe kidney injury. At these later timepoints, cTNFR1/2 levels positively correlate with remaining kidney injury. During the AKI-to-CKD transition, elevations of TNFR1/2 kidney expression and of cTNFR2 levels correlate with kidney fibrosis levels. In conclusion, our data demonstrate that kidney injury drives acute increases in cTNFR1/2 serum levels, which negatively correlate with kidney function. Sustained TNFR1/2 elevations after kidney injury during AKI-to-CKD transition reflect persistent tissue injury and progression to kidney fibrosis.

The interplay between inflammatory cytokines and cardiometabolic disease: bi-directional mendelian randomisation study

ObjectiveTo leverage large scale genetic association data to investigate the interplay between circulating cytokines and cardiometabolic traits, and thus identifying potential therapeutic targets.DesignBi-directional Mendelian randomisation study.SettingGenome-wide association studies from three...

Circulating expression patterns of TL1A and FFAR2 in patients with stable and unstable angina

Background and aimThe primary factor in sudden cardiac death is coronary artery disease. We intended to discover the diagnostic worth of circulating tumor necrosis factor like cytokine 1A (TL1A) and free fatty acid receptor 2 (FFAR2) as early, noninvasive indicators for individuals with stable angina (SA) and unstable angina (UA).MethodsIn all, 90 people were enrolled in the current case–control study: 30 patients with SA, 30 patients with UA, and 30 healthy volunteers. Circulating TL1A and FFAR2 gene expression levels were evaluated by quantitative real-time polymerase chain reaction (qRT-PCR). FBG, TC, TG, and HDL-C were assessed by spectrophotometry, while hs-CRP and troponin T were measured by ELISA.ResultsCirculating TL1A expression was significantly elevated in SA (P < 0.001) and UA patients (P < 0.001) as compared to controls and also was significantly higher in UA patients (P < 0.001) as compared to SA patients. Circulating FFAR2 expression was significantly decreased in SA (P < 0.001) and UA patients (P < 0.001) in comparison with controls and was significantly lowered in UA patients (P = 0.001) in comparison with SA patients. Our results show that TL1A and FFAR2 were sensitive and specific biomarkers for discriminating SA patients from controls. Moreover, TL1A and FFAR2 displayed a remarkable ability to distinguish UA from SA. Multivariate regression analysis revealed that TL1A, FFAR2, FBG, TC, TG, LDL-C, and Troponin T were independent risk factors for SA, while TL1A, TG, and hs-CRP were independent risk factors for UA. TL1A has a significant positive correlation with LDL-C (r = 0.406, P = 0.001), hs-CRP (r = 0.673, P < 0.001), and troponin T (r = 0.653, P < 0.001). There was a significant inverse relationship between FFAR2 and each of TL1A (r = − 0.858, P < 0.001), FBG (r = − 0.325, P = 0.011), TC(r = − 0.306, P = 0.017), TG (r = − 0.368, P = 0.004), LDL-C (r = − 0.413, P = 0.001), hs-CRP (r = − 0.737, P < 0.001), and troponin T (r = − 0.715, P < 0.001).ConclusionGene expression of TL1A and FFAR2 is a good new blood-based molecular indicator for early detection of SA and UA. Early detection of a possible UA is crucial for initiating appropriate treatment that results in better patient health.

Plasma Circulating Tumor Necrosis Factor Receptors at Multiple Time Points Can Predict the Outcome of Severe Acute Kidney Injury

Introduction: This prospective cohort study investigated the clinical role of circulating tumor necrosis factor receptor (cTNFR) levels as prognostic biomarkers in severe acute kidney injury (AKI) patients requiring continuous renal replacement therapy (CRRT). Methods: We enrolled 136 patients from 7 hospitals participating in the VENUS (VolumE maNagement Under body composition monitoring in critically ill patientS on CRRT) trial from July 2017 to October 2019. The levels of cTNFR1 and cTNFR2 were measured using plasma samples collected on days 0 (D0), 2 (D2), and 7 (D7). Patients were divided into high- and low-cTNFR groups based on their receptor concentrations. Results: D0 concentrations of cTNFR1 and cTNFR2 were positively correlated with one another (R2 = 0.37, p < 0.001). The high-cTNFR1 group displayed a higher in-hospital mortality rate than the low-TNFR1 group (p = 0.002). Moreover, the mortality rate was significantly higher in the high-TNFR1 group than in the low-TNFR1 group after adjusting for age, sex, and acute physiology, and chronic health evaluation II scores (hazard ratio 1.82, 95% confidence interval 1.09–3.03, p = 0.025). D2 and D7 cTNFR1 levels were also associated with in-hospital mortality; contrastingly, cTNFR2 levels were not associated with this outcome. Additionally, patients were divided into three groups according to the change in cTNFR levels from D0 to D2 (ΔcTNFR). Those in the highest ΔcTNFR tertile had a higher mortality rate than the remaining patients (p = 0.033 for ΔcTNFR1; p = 0.025 for ΔcTNFR2). Patients who underwent AKI-to-chronic kidney disease transition had higher concentrations of cTNFR1 (p = 0.014). Discussion/Conclusion: Plasma cTNFR1 concentrations at CRRT initiation and changes in cTNFR1 and 2 levels immediately following CRRT initiation are significant biomarkers for predicting the outcomes of patients with severe AKI.

Circulating tumor necrosis factor receptors are associated with mortality and disease severity in COVID-19 patients.

BackgroundAlthough hyperinflammatory response influences the severity of coronavirus disease 2019 (COVID-19), little has been reported about the utility of tumor necrosis factor (TNF)-related biomarkers in reflecting the prognosis. We examined whether TNF receptors (TNFRs: TNFR1, TNFR2) and progranulin (PGRN) levels, in addition to interleukin 6 (IL-6) and C-reactive protein (CRP), are associated with mortality or disease severity in COVID-19 patients.MethodsThis retrospective study was conducted at Juntendo University Hospital. Eighty hospitalized patients with various severities of COVID-19 were enrolled. Furthermore, serum levels of TNF-related biomarkers were measured using enzyme-linked immunosorbent assay.ResultsTwenty-five patients died during hospitalization, and 55 were discharged. The median (25th and 75th percentiles) age of the study patients was 70 (61–76) years, 44 (55.0%) patients were males, and 26 (32.5%) patients had chronic kidney disease (CKD). When comparing with patients who received and did not receive treatment at the intensive care unit (ICU), the former had a higher tendency of being male and have diabetes, hypertension, and CKD; had higher levels of white blood cells, D-dimer, and lactate dehydrogenase; and had lower body mass index, estimated glomerular filtration rate, and lymphocyte counts. Significant differences were observed in TNFR, PGRN, IL-6, and CRP levels between each severity (mild–severe) group. Furthermore, the serum levels of TNFR, IL-6, and CRP, but not PGRN, in ICU patients were significantly higher than in the patients who were not admitted to the ICU. Multivariate logistic regression analysis demonstrated that high levels of TNFR2 were only associated with mortality in patients with COVID-19 even after adjustment for relevant clinical parameters.ConclusionsHigh TNFR2 level might be helpful for predicting mortality or disease severity in patients with COVID-19.

Overnight sleeping heart rate variability of Army recruits during a 12-week basic military training course

PurposeThis study aimed to quantify sleeping heart rate (HR) and HR variability (HRV) alongside circulating tumor necrosis factor alpha (TNFα) concentrations during 12-week Basic Military Training (BMT). We hypothesised that, despite a high allostatic load, BMT would increase cardiorespiratory fitness and HRV, while lowering both sleeping HR and TNFα in young healthy recruits.MethodsSixty-three recruits (18–43 years) undertook ≥ 2 overnight cardiac frequency recordings in weeks 1, 8 and 12 of BMT with 4 h of beat-to-beat HR collected between 00:00 and 06:00 h on each night. Beat-to-beat data were used to derive HR and HRV metrics which were analysed as weekly averages (totalling 8 h). A fasted morning blood sample was collected in the equivalent weeks for the measurement of circulating TNFα concentrations and predicted VO2max was assessed in weeks 2 and 8.ResultsPredicted VO2max was significantly increased at week 8 (+ 3.3 ± 2.6 mL kg−1 min−1; p < 0.001). Sleeping HR (wk1, 63 ± 7 b min−1) was progressively reduced throughout BMT (wk8, 58 ± 6; wk12, 55 ± 6 b min−1; p < 0.01). Sleeping HRV reflected by the root mean square of successive differences (RMSSD; wk1, 86 ± 50 ms) was progressively increased (wk8, 98 ± 50; wk12, 106 ± 52 ms; p < 0.01). Fasted circulating TNFα (wk1, 9.1 ± 2.8 pg/mL) remained unchanged at wk8 (8.9 ± 2.5 pg/mL; p = 0.79) but were significantly reduced at wk12 (8.0 ± 2.4 pg/mL; p < 0.01).ConclusionIncreased predicted VO2max, HRV and reduced HR during overnight sleep are reflective of typical cardiorespiratory endurance training responses. These results indicate that recruits are achieving cardiovascular health benefits despite the high allostatic load associated with the 12-week BMT.

Immunology study and the Assessment of parameters in difference Age, Sex of stage resistance infection leishmaniasis in Dayla

The Leishmania parasite belonged to trypanosomatidae family,. Cutaneous leishmaniasis (CL)and visceral leishmaniasis (VL) are endemic in Iraq as one of the neglected tropical diseases. The current drugswhich are used as antileishaminial treatment characterized by enormous side effects including their toxicity tohuman, long term treatment, liver problems, hugely cost. Therefore, there is a necessity to find an alternativetreatment marked as low cost, more specific against parasite’s stages, Tumor necrosis factor-alpha (TNF-α), acytokine that generated by the innate immune response to CL infection, can influence disease clearance in thehuman host. The effect of this pro-inflammatory cytokine in CL ulcer development during the infection is not wellestablished. The current study was conducted on 88 individaul of both sexes, they were from Diyala province andthe capital Baghdad, during the period from October 2020 to February 2021.All suspected cutaneous or visceral patients involved in this study were prediagnosed in the laboratory beforeprocessing Tumor Necrosis Factor-alpha (TNF-α) and Adenosine Deaminase Enzyme (ADA) by ELISAcolorimetric detection.Total number of confirmed leishmaniasis patients were (n=57) cutaneous patients and (n=16) visceral patients,collected from different hospitals in Diyala province and Baghdad. Positive CL or VL samples were confirmed bymicroscopic Giemsa staining, In this study, the level of circulating tumor necrosis factor alpha and adenosinedeaminase enzyme levels were detected in CL patients of newly diagnosed infection and in patients undergoingdifferent doses of treatment, 2nd and 3rd Pentostam trail-treatment, in addition, VL patients of newly diagnosedinfection with no treatment; in comparison to control subjects.Regardless the type of leishmaniasis and according to age, the results showed that TNF-α concentration was higherin patients less than 15 years old, in comparison with other age group over 15 years (15-60) years old, which was1169.899 ng/ml and 961.206 ng/ml respectively. While according to sex, the higher concentration of TNF-α wasrecorded in female rather than male, 1030.243 ng/ml and 996.458 ng/mlRegarding ADA enzyme, the highest enzyme activity also recorded in the age group of 1-14 years old, which was4.749 nanomol/minute/µg, in comparison of patients between 15-60 years old, which was 3.706nanomol/minute/µg. While according to sex, the maximum enzyme activity was seen in male rather than female(4.296, 4.483) nanomol/minute/µg, respectively. The perceived rise of TNF-α and ADA serum levels may giveinsights into this pro-inflammatory cytokine as a biomarker in prognosis and tracking disease progression.

Markers of systemic inflammation are positively associated with influenza vaccine antibody responses with a possible role for ILT2(+)CD57(+) NK-cells

BackgroundWith increasing age, overall health declines while systemic levels of inflammatory mediators tend to increase. Although the underlying mechanisms are poorly understood, there is a wealth of data suggesting that this so-called “inflammaging” contributes to the risk of adverse outcomes in older adults. We sought to determine whether markers of systemic inflammation were associated with antibody responses to the seasonal influenza vaccine.ResultsOver four seasons, hemagglutination inhibition antibody titres and ex vivo bulk peripheral blood mononuclear cell (PBMC) responses to live influenza viruses assessed via interferon (IFN)-γ/interleukin (IL)-10 production, were measured pre- and 4-weeks post-vaccination in young adults (n = 79) and older adults randomized to standard- or high-dose inactivated vaccine (n = 612). Circulating tumour necrosis factor (TNF), interleukin (IL)-6 and C-reactive protein (CRP) were also measured pre-vaccination. Post-vaccination antibody titres were significantly associated with systemic inflammatory levels; specifically, IL-6 was positively associated with A/H3N2 titres in young adults (Cohen’s d = 0.36), and in older high-dose, but not standard-dose recipients, all systemic inflammatory mediators were positively associated with A/H1N1, A/H3N2 and B titres (d = 0.10–0.45). We further show that the frequency of ILT2(+)CD57(+) CD56-Dim natural killer (NK)-cells was positively associated with both plasma IL-6 and post-vaccination A/H3N2 titres in a follow-up cohort of older high-dose recipients (n = 63). Pathway analysis suggested that ILT2(+)CD57(+) Dim NK-cells mediated 40% of the association between IL-6 and A/H3N2 titres, which may be related to underlying participant frailty.ConclusionsIn summary, our data suggest a complex relationship amongst influenza vaccine responses, systemic inflammation and NK-cell phenotype in older adults, which depends heavily on age, vaccine dose and possibly overall health status. While our results suggest that “inflammaging” may increase vaccine immunogenicity in older adults, it is yet to be determined whether this enhancement contributes to improved protection against influenza disease.

PP6 deficiency in mice with KRAS mutation and Trp53 loss promotes early death by PDAC with cachexia-like features.

To examine effects of PP6 gene (Ppp6c) deficiency on pancreatic tumor development, we developed pancreas‐specific, tamoxifen‐inducible Cre‐mediated KP (KRAS(G12D) plus Trp53‐deficient) mice (cKP mice) and crossed them with Ppp6cflox / flox mice. cKP mice with the homozygous Ppp6c deletion developed pancreatic tumors, became emaciated and required euthanasia within 150 days of mutation induction, phenotypes that were not seen in heterozygous or wild‐type (WT) mice. At 30 days, a comparative analysis of genes commonly altered in homozygous versus WT Ppp6c cKP mice revealed enhanced activation of Erk and NFκB pathways in homozygotes. By 80 days, the number and size of tumors and number of precancerous lesions had significantly increased in the pancreas of Ppp6c homozygous relative to heterozygous or WT cKP mice. Ppp6c −/− tumors were pathologically diagnosed as pancreatic ductal adenocarcinoma (PDAC) undergoing the epithelial–mesenchymal transition (EMT), and cancer cells had invaded surrounding tissues in three out of six cases. Transcriptome and metabolome analyses indicated an enhanced cancer‐specific glycolytic metabolism in Ppp6c‐deficient cKP mice and the increased expression of inflammatory cytokines. Individual Ppp6c −/− cKP mice showed weight loss, decreased skeletal muscle and adipose tissue, and increased circulating tumor necrosis factor (TNF)‐α and IL‐6 levels, suggestive of systemic inflammation. Overall, Ppp6c deficiency in the presence of K‐ras mutations and Trp53 gene deficiency promoted pancreatic tumorigenesis with generalized cachexia and early death. This study provided the first evidence that Ppp6c suppresses mouse pancreatic carcinogenesis and supports the use of Ppp6c‐deficient cKP mice as a model for developing treatments for cachexia associated with pancreatic cancer.

Anti-inflammatory and anti-apoptotic effects of N-acetylcysteine in diabetic rat corneal epithelium.

To characterize the anti-inflammatory and anti-apoptotic effects of N-acetylcysteine (NAC) in streptozotocin (STZ)-induced diabetic rat corneal epithelium and human corneal epithelial cells (HCECs) exposed to a high-glucose environment. HCECs were incubated in 0, 5, 50 mmol/L glucose medium, or 50 mmol/L glucose medium with NAC for 24h. Diabetes was induced in rats by intraperitoneal injection of 65 mg/kg STZ and some of these rats were topically administered NAC to corneas with 3 mice per group. We characterized receptor for advanced glycation end-products (RAGE) expression using immunofluorescence, and interleukin (IL)-1β and cleaved caspase-3 (CCAP-3) expression using immunohistochemistry. Circulating tumor necrosis factor (TNF)-α concentration was measured by ELISA and cleaved poly-ADP ribose polymerase (PARP) concentration was quantified by Western blotting. Apoptotic cells were detected using TUNEL assay and annexin V and propidium iodide staining. Diabetic rats had higher expression of RAGE (2.46±0.13 fold), IL-1β, and CCAP-3 in apoptotic cells of their corneas than control rats. The expression of RAGE (1.83±0.11 fold), IL-1β, and CCAP-3, and the number of apoptotic cells, were reduced by topical NAC treatment. HCECs incubated in 50 mmol/L glucose medium showed high concentrations of TNF-α (310±2.00 pg/mL) and cleaved PARP (7.43±0.56 fold), and more extensive apoptosis than cells in 50 mmol/L glucose medium. However, the addition of NAC reduced the concentrations of TNF-α (153.67±2.31 pg/mL) and cleaved PARP (5.55±0.31 fold) and the number of apoptotic cells. NAC inhibits inflammation and apoptosis in the corneas of diabetic rats and HCECs maintained in a high-glucose environment.

Inflammation-induced left ventricular fibrosis is partially mediated by tumor necrosis factor-α.

ObjectiveTo determine the mechanisms of inflammation‐induced left ventricular (LV) remodeling and effects of blocking circulating tumor necrosis factor alpha (TNF‐α) in a model of systemic inflammation.MethodsSeventy Sprague‐Dawley rats were divided into three groups: the control group, the collagen‐induced arthritis (CIA) group, and the anti‐TNF‐α group. Inflammation was induced in the CIA and anti‐TNF‐α groups. Following the onset of arthritis, the anti‐TNF‐α group received the TNF‐α inhibitor, etanercept, for 6 weeks. LV geometry and function were assessed with echocardiography. Circulating inflammatory markers were measured by ELISA and LV gene expression was assessed by comparative TaqMan® polymerase chain reaction.ResultsThe LV relative gene expression of pro‐fibrotic genes, transforming growth factor β (TGFβ) (p = 0.03), collagen I (Col1) (p < 0.0001), and lysyl oxidase (LOX) (p = 0.002), was increased in the CIA group compared with controls, consistent with increased relative wall thickness (p = 0.0009). Col1 and LOX expression in the anti‐TNF‐α group were similar to controls (both, p > 0.05) and tended to be lower compared to the CIA group (p = 0.06 and p = 0.08, respectively), and may, in part, contribute to the decreased relative wall thickness in the anti‐TNF‐α group compared to the CIA group (p = 0.03). In the CIA group, the relative gene expression of matrix metalloproteinase 2 (MMP2) and MMP9 was increased compared to control (p = 0.04) and anti‐TNF‐α (p < 0.0001) groups, respectively.ConclusionChronic systemic inflammation induces fibrosis and dysregulated LV extracellular matrix remodeling by increasing local cardiac pro‐fibrotic gene expression, which is partially mediated by TNF‐α. Inflammation‐induced LV diastolic dysfunction is likely independent of myocardial fibrosis.

Circulating and Myocardial Cytokines Predict Cardiac Structural and Functional Improvement in Patients With Heart Failure Undergoing Mechanical Circulatory Support.

BackgroundRecent prospective multicenter data from patients with advanced heart failure demonstrated that left ventricular assist device (LVAD) support combined with standard heart failure medications, induced significant cardiac structural and functional improvement, leading to high rates of LVAD weaning in selected patients. We investigated whether preintervention myocardial and systemic inflammatory burden could help identify the subset of patients with advanced heart failure prone to LVAD‐mediated cardiac improvement to guide patient selection, treatment, and monitoring.Methods and ResultsNinety‐three patients requiring durable LVAD were prospectively enrolled. Myocardial tissue and blood were acquired during LVAD implantation, for measurement of inflammatory markers. Cardiac structural and functional improvement was prospectively assessed via serial echocardiography. Eleven percent of the patients showed significant reverse remodeling following LVAD support (ie, responders). Circulating tumor necrosis factor alpha, interleukin (IL)‐4, IL‐5, IL‐6, IL‐7, IL‐13, and interferon gamma were lower in responders, compared with nonresponders (P<0.05, all comparisons). The myocardial tissue signal transducer and activator of transcription‐3, an inflammatory response regulator, was less activated in responders (P=0.037). Guided by our tissue studies and a multivariable dichotomous regression analysis, we identified that low levels of circulating interferon gamma (odds ratio [OR], 0.06; 95% CI, 0.01–0.35) and tumor necrosis factor alpha (OR, 0.05; 95% CI, 0.00–0.43), independently predict cardiac improvement, creating a 2‐cytokine model effectively predicting responders (area under the curve, 0.903; P<0.0001).ConclusionsBaseline myocardial and systemic inflammatory burden inversely correlates with cardiac improvement following LVAD support. A circulating 2‐cytokine model predicting significant reverse remodeling was identified, warranting further investigation as a practical preintervention tool in identifying patients prone to LVAD‐mediated cardiac improvement and device weaning.

Circulating tumor necrosis factor-α levels in non-alcoholic fatty liver disease: A systematic review and a meta-analysis.

To synthesize data on circulating tumor necrosis factor (TNF)-α levels between patients with histologically confirmed non-alcoholic fatty liver disease (NAFLD) (simple steatosis or non-alcoholic fatty liver [NAFL] and/or non-alcoholic steatohepatitis [NASH]) and controls. We performed a systematic search in PubMed, Scopus, and Cochrane Library. Fifty-six studies, published between 2003 and 2019, were finally included, reporting data from 5848 individuals (1634 controls and 4214 NAFLD patients). Higher circulating TNF-α levels were observed in NAFLD patients than controls (standardized mean difference [SMD] 0.84; 95% confidence interval [95% CI] 0.59-1.09), NAFL patients than controls (SMD 0.56; 95% CI 0.27-0.85), NASH patients than controls (SMD 0.93; 95% CI 0.64-1.22), and NASH than NAFL patients (SMD 0.31; 95% CI 0.16-0.46). There were only minimal changes in the comparisons between groups after excluding studies with morbidly obese populations (n=11), or pediatric/adolescent populations (n=6), or other than enzyme-linked immunosorbent assay method of TNF-α measurement (n=8). There was high heterogeneity among studies in all comparisons, which was not essentially affected after sensitivity analyses. The meta-regression analysis revealed that the male ratio was positively associated with TNF-α SMD in the comparison between patients with NASH and NAFL (beta=0.809; 95% CI 0.052-1.566) and accounted for 36% (P=0.037) of the heterogeneity in this pair of comparison. TNF-α SMD was not associated with age, body mass index, and alanine aminotransferase in any pair of comparisons. Circulating TNF-α levels were higher in patients with NAFLD compared with controls. Higher levels of circulating TNF-α were also associated with the severity of NAFLD.

Association Between Kidney Function Decline and Baseline TNFR Levels or Change Ratio in TNFR by Febuxostat Chiefly in Non-diabetic CKD Patients With Asymptomatic Hyperuricemia

Background: The levels of circulating tumor necrosis factor receptor (TNFR) 1 and 2 help predict the future decline of estimated glomerular filtration rate (eGFR) chiefly in patients with diabetes. It has been recently reported that the change ratio in TNFR1 by SGLT2 inhibitor treatment is also related with future GFR decline in patients with diabetes. The aims of this study are to investigate the association between baseline TNFR levels and early change in TNFR levels by the non-purine selective xanthine oxidase inhibitor, febuxostat, and future eGFR decline chiefly in chronic kidney disease (CKD) patients without diabetes.Methods: We conducted a post-hoc analysis of the FEATHER study on patients with asymptomatic hyperuricemia and CKD stage 3, who were randomly assigned febuxostat 40 mg/day or matched placebo. This analysis included 426 patients in whom baseline stored samples were available. Serum TNFR levels at baseline were measured using enzyme-linked immunosorbent assay. Those levels were also measured using 12-week stored samples from 197 randomly selected patients.Results: Compared with placebo, short-term febuxostat treatment significantly decreased the median percent change from baseline in serum uric acid (−45.05, 95% CI −48.90 to −41.24 mg/dL), TNFR1 (1.10, 95% CI−2.25 to 4.40), and TNFR2 (1.66, 95% CI −1.72 to 4.93), but not TNFR levels. Over a median follow-up of 105 weeks, 30 patients (7.0%) experienced 30% eGFR decline from baseline. In the Cox multivariate model, high levels of baseline TNFR predicted a 30% eGFR decline, even after adjusting for age, sex, systolic blood pressure, high sensitivity C-reactive protein, uric acid, and presence or absence of febuxostat treatment and diabetes, in addition to baseline albumin to creatinine ratio and eGFR.Conclusion: Early change in circulating TNFR levels failed to predict future eGFR decline; however, regardless of febuxostat treatment, the elevated baseline level of TNFR was a strong predictor of 30% eGFR decline even in chiefly non-diabetic CKD patients with asymptomatic hyperuricemia.

Correction of redox metabolism and the relationship of markers of systemic chronic inflammation with a measure of overall survival in cancer patients with multiorgan resections

Background. According to the literature, multiorgan resections are carried out with the most radical removal of healthy tissue. Therefore, there is a need for the most favorable preparation of the patient with perioperative therapy to reduce further complications with obtaining improved clinical and pathological prognostic indicators to increase the overall survival. Purpose: correction of redox metabolism based on the data of the oxidative modification of proteins, degree of their catabolic reaction, and data on the enzymatic state and lipid peroxidation in cancer patients with multiorgan resections on the gastrointestinal tract under conditions of perioperative intensive care. Materials and methods. The study involved 117 cancer patients aged 67.6 ± 3.7 years with locally advanced tumor processes of the gastrointestinal tract. Studies have been conducted on the enzymatic state, lipid peroxidation and oxidative modification of proteins, both in terms of the degree of fragmentation of their products in spontaneous and iron-induced reactions, and the level of medium-weight protein molecules. Serum levels of circulating tumor necrosis factor alpha, interleukin-6 and -8 were determined. Survival analysis was performed using the Kaplan-Meier method. Results. The study of patients has shown an improvement in the indicators of oxidative modification of proteins and lipid peroxidation. Survival in cancer patients with multiorgan resections demonstrated dependence on the levels of tumor necrosis factor alpha, interleukin-6 and -8 in the blood serum. Conclusions. Conducting perioperative intensive care makes it possible to reliably restore indicators of the enzymatic state, lipid peroxidation and oxidative protein modification products (on the fourth day and second week, p &lt; 0.05). This gives us grounds for recommending the determination of these parameters in the group of cancer patients and the implementation of metabolic intensive care. In the group of L-ornithine L-aspartate and quercetin combination with povidone, the lowest indicators of systemic chronic inflammation and the best overall survival were found.

Precision medicine approaches for diabetic kidney disease: opportunities and challenges.

The prevalence of end-stage kidney disease (ESKD) continuously increases worldwide. The increasing prevalence parallels the growth in the number of people with diabetes, which is the leading cause of ESKD. Early diagnosis of chronic kidney disease (CKD) in patients with diabetes and appropriate intervention is important to delay the progression of kidney function decline and prevent ESKD. Rate of CKD progression and response to treatment varies among patients with diabetes, highlighting the need to tailor individual treatment. In this review, we describe recent advances and areas for future studies with respect to precision medicine in diabetic kidney disease (DKD). DKD is a multi-factorial disease that is subject in part to genetic heritability, but is also influenced by various exogenous mediators, such as environmental or dietary factors. Genetic testing so far has limited utility to facilitate early diagnosis, classify progression or evaluate response to therapy. Various biomarker-based approaches are currently explored to identify patients at high risk of ESKD and to facilitate decision-making for targeted therapy. These studies have led to discovery and validation of a couple of inflammatory proteins such as circulating tumour necrosis factor receptors, which are strong predictors of kidney disease progression. Moreover, risk and drug-response scores based on multiple biomarkers are developed to predict kidney disease progression and long-term drug efficacy. These findings, if implemented in clinical practice, will pave the way to move from a one-size-fits-all to a one-fit-for-everyone approach.

Impact of heat stress and a feed supplement on hormonal and inflammatory responses of dairy cows

The aim of this trial was to evaluate the effects of an immunomodulatory supplement (OmniGen AF, OG; Phibro Animal Health Corp.) and heat stress on hormonal, inflammatory, and immunological responses of lactating dairy cows. Sixty multiparous Holstein cows were randomly assigned to 4 treatments in a 2 × 2 factorial arrangement using 2 environments: cooled using fans and misters, or noncooled, and 2 top-dressed feed supplements (56 g/d): OG or a placebo (CTL). Temperature-humidity index averaged 78 during the 8-wk trial. Blood was drawn to analyze cortisol, prolactin, and circulating tumor necrosis factor (TNF)-α and IL-10. Peripheral blood mononuclear cells (PBMC) were isolated and stimulated with hydrocortisone, prolactin, or lipopolysaccharide (LPS), individually or in several combinations, to assess induced proliferation and cytokine production. At d 52, 6 cows per treatment were injected i.v. with an LPS bolus (ivLPS) to assess hormone and cytokine responses. For cooled cows, feeding OG increased plasma cortisol concentration relative to CTL. Noncooled cows fed CTL had lower circulating TNF-α concentrations than noncooled-OG and cooled-CTL cows, with cooled-OG intermediate. Hydrocortisone+LPS-stimulated PBMC from OG cows tended to proliferate more than CTL. Relative to cooled cows, PBMC from noncooled cows produced more TNF-α and IL-10 when stimulated with LPS. Following ivLPS, cooled-OG cows had a greater cortisol response than the other treatments. In conclusion, OG supplementation enhanced cortisol release under basal condition and induced inflammation with cooling compared with CTL. This suggests that heat stress inhibits OG-mediated cortisol release. Heat stress seemed to enhance the inflammatory responses of PBMC from lactating cows. However, OG supplementation promoted PBMC proliferation under stress, or in the presence of hydrocortisone.

Splenic Nerve Neuromodulation Reduces Inflammation and Promotes Resolution in Chronically Implanted Pigs.

Neuromodulation of the immune system has been proposed as a novel therapeutic strategy for the treatment of inflammatory conditions. We recently demonstrated that stimulation of near-organ autonomic nerves to the spleen can be harnessed to modulate the inflammatory response in an anesthetized pig model. The development of neuromodulation therapy for the clinic requires chronic efficacy and safety testing in a large animal model. This manuscript describes the effects of longitudinal conscious splenic nerve neuromodulation in chronically-implanted pigs. Firstly, clinically-relevant stimulation parameters were refined to efficiently activate the splenic nerve while reducing changes in cardiovascular parameters. Subsequently, pigs were implanted with a circumferential cuff electrode around the splenic neurovascular bundle connected to an implantable pulse generator, using a minimally-invasive laparoscopic procedure. Tolerability of stimulation was demonstrated in freely-behaving pigs using the refined stimulation parameters. Longitudinal stimulation significantly reduced circulating tumor necrosis factor alpha levels induced by systemic endotoxemia. This effect was accompanied by reduced peripheral monocytopenia as well as a lower systemic accumulation of CD16+CD14high pro-inflammatory monocytes. Further, lipid mediator profiling analysis demonstrated an increased concentration of specialized pro-resolving mediators in peripheral plasma of stimulated animals, with a concomitant reduction of pro-inflammatory eicosanoids including prostaglandins. Terminal electrophysiological and physiological measurements and histopathological assessment demonstrated integrity of the splenic nerves up to 70 days post implantation. These chronic translational experiments demonstrate that daily splenic nerve neuromodulation, via implanted electronics and clinically-relevant stimulation parameters, is well tolerated and is able to prime the immune system toward a less inflammatory, pro-resolving phenotype.