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Background and Aim: Endometriosis affects the ovaries and causes a decrease in the oocyte quality during endometrial receptivity. During the development of ovarian follicles, paracrine communication occurs between granulosa cells and oocytes. This study was conducted to determine the effects of bone marrow mesenchymal stem cell transplantation on tumor necrosis factor-alpha (TNF-α) receptor 1 (TNFR1) expression, granulosa cell apoptosis, and folliculogenesis in endometriosis mouse models. Materials and Methods: This study involved 42 female mice, which were divided into three groups: Healthy mice (T0), endometriosis mice without transplantation (T1), and endometriosis mice with bone marrow mesenchymal stem cell transplantation (T2). The mice were injected intraperitoneally with endometrial fragments (200 μL) to become endometriosis models. On day 15, the endometriosis models received mesenchymal stem cells. Sample collection was performed on day 29. Granulosa cell apoptosis and TNFR1 expression were examined using immunohistochemical staining, and folliculogenesis was assessed using hematoxylin and eosin staining of ovary samples. The data obtained from both examinations were statistically analyzed using Statistical Package for the Social Sciences. Results: The results showed that TNFR1 expression is significantly decreased in T2 (p

Background and aimsTumor necrosis factor receptor type 1 (TNFR1) is associated with kidney disease and mortality risk in various populations. Whether or not kidney function mediates mortality risk is unknown. We evaluated associations of TNFR1 levels with measures of kidney function, cardiovascular events, and mortality in a population of veterans with stable ischemic heart disease.MethodsTNFR1 was measured from baseline serum samples in the Heart and Soul Study; elevated levels were defined by the highest quartile (Q4, >3.4 ng/ml). We evaluated associations of high TNFR1 with baseline estimated glomerular filtration rate (eGFR) and urine albumin to creatinine ratio (ACR) and with longitudinal changes in eGFR (rapid loss), as well as with incident myocardial infarction (MI), heart failure hospitalizations (HF), and mortality over a median follow-up time of 8.9 years. Covariates included demographics and comorbid conditions.ResultsAmong 985 participants who had TNFR1 measurements, median TNFR1 was 2.33 ng/ml (IQR 1.8-3.1). Relative to Q1, Q4 had higher risk of eGFR

Background/Aim. Cholesteatoma is characterized by progressive growth with the erosion of surrounding bone due to pressure effects, enzymatic activity and activation of osteoclasts. The aim of this study was to examine the expression levels of tumor necrosis factor (TNF)-alpha receptor 2 (TNF R2) and interleukin-1 (IL-1) in chronic otitis media (COM) with and without acquired cholesteatoma and correlate them with the degree of bone destruction. Methods. The study included 178 patients of both sexes, aged 5–75 years, who underwent microsurgical treatment for COM, with and without cholesteatoma at the Ear, Nose and Throat Department, University Clinical Center of Republika Srpska (UCC RS), Banja Luka from 2015 to 2018. Based on cholesteatoma presence, the patients with COM were divided into two groups: with cholesteatoma (CCOM) (n = 97) and without cholesteatoma (COMWC) (n = 81). Samples of cholesteatoma perimatrix in the CCOM group and tympanic cavity inflamed mucosa in the COMWC group were collected intraoperatively. Intraoperative exploration of the middle ear included the status of the ossicular chain, individual ossicles, osseous walls of the external auditory canal (EAC) and tympanic cavity. Expression levels of TNF R2 and IL-1 were investigated by immunohistochemical analysis of tissue samples obtained during ear surgery. Results. The correlation between the level of osteodestruction and the presence of cholesteatoma was significant (p < 0.01). Elevated expression levels of TNF R2 and IL-1 were most frequent in CCOM patients with osteodestruction. The probability of osteodestruction of EAC and tympanic cavity walls was significantly higher in patients with high TNF R2 expression (p < 0.05). With respect to IL-1 expression levels, no significant correlation with the described pathomorphological changes was observed. Correlation between TNF R2 and IL-1 expressions and ossicular chain destruction was significant (p < 0.01). Conclusion. Cholesteatoma presence and elevated expression levels of TNF R2 and IL-1 in COM patients are significantly correlated. Expression levels of TNF R2 and IL-1 in acquired cholesteatoma tissue have a potential clinical significance for the occurrence of bone destruction compared to expression levels in inflamed mucosa of the tympanic cavity.

Tumor necrosis factor -alpha (TNFα) is strongly associated with fatty liver disease (i.e, hepatosteatosis). Cytokine production has been thought of as a consequence of hepatic lipid accumulation which becomes a critical factor in the development of chronic liver pathologies as well as insulin resistance. The purpose of this study was to test the hypothesis that TNFα directly regulates lipid metabolism in liver in the mutant peroxisome-proliferator activated receptor-alpha (PPARα -/- ) mouse model with robust hepatic lipid accumulation. At 10 weeks of age, TNFα and TNF receptor 1 expression are increased in livers of PPARα -/- mice compared to wild type. PPARα -/- mice were then crossed with mice lacking the receptor for TNFα receptor 1 (TNFR1 -/- ). Wild type, PPARα -/- , TNFR1 -/- , PPARα -/- x TNFR1 -/- mice were housed on ad-libitum standard chow diet for up to 40 weeks. Increases in hepatic lipid and liver injury and metabolic disruption associated with PPARα ablation were largely blunted when PPARα -/- mice were crossed with TNFR1 -/- mice. These data support the hypothesis that TNFR1 signaling is critical for accumulation of lipid in liver. Therapies that reduce pro-inflammatory responses, namely TNFα, could have important clinical implications to reduce hepatosteatosis and progression of severe liver disease.

Background: End-stage liver disease caused by non-alcoholic steatohepatitis (NASH) is the second leading indication for liver transplantation. To date, only moderately effective pharmacotherapies exist to treat NASH. Understanding the pathogenesis of NASH is therefore crucial for the development of new therapies. The inflammatory cytokine tumor necrosis factor alpha (TNF-α) is important for the progression of liver disease. TNF signaling via TNF receptor 1 (TNFR1) has been hypothesized to be important for the development of NASH and hepatocellular carcinoma in whole-body knockout animal models., Aim: To investigate the role of TNFR1 signaling in hepatocytes for steatohepatitis development in a mouse model of diet-induced NASH., Methods: NASH was induced by a western-style fast-food diet in mice deficient for TNFR1 in hepatocytes (TNFR1 ΔHEP ) and their wild-type littermates (TNFR1 fl/fl ). Glucose tolerance was assessed after 18 wk and insulin resistance after 19 wk of feeding. After 20 wk mice were assessed for features of NASH and the metabolic syndrome such as liver weight, liver steatosis, liver fibrosis and markers of liver inflammation., Results: Obesity, liver injury, inflammation, steatosis and fibrosis was not different between TNFR1 ΔHEP and TNFR1 fl/fl mice. However, Tnfr1 deficiency in hepatocytes protected against glucose intolerance and insulin resistance., Conclusion: Our results indicate that deficiency of TNFR1 signaling in hepatocytes does not protect from diet-induced NASH. However, improved insulin resistance in this model strengthens the role of the liver in glucose homeostasis., Competing Interests: Conflict-of-interest statement: Schnabl B has been consulting for Ferring Research Institute, HOST Therabiomics, Intercept Pharmaceuticals and Patara Pharmaceuticals. Schnabl B’s institution UC San Diego has received research support from Axial Biotherapeutics, BiomX, CymaBay Therapeutics, NGM Biopharmaceuticals, and Synlogic Operating Company., (©The Author(s) 2020. Published by Baishideng Publishing Group Inc. All rights reserved.)

BACKGROUND: Adipose tissue inflammation and dysregulated adipokine secretion are implicated in obesity-related insulin resistance and type 2 diabetes. We evaluated the use of serum adiponectin, an anti-inflammatory adipokine, and several proinflammatory adipokines, as biomarkers of diabetes risk and whether they add to traditional risk factors in diabetes prediction. METHODS: We studied 1300 non-diabetic subjects from the prospective Hong Kong Cardiovascular Risk Factor Prevalence Study (CRISPS). Serum adiponectin, tumor necrosis factor-alpha receptor 2 (TNF-α R2), interleukin-6 (IL-6), adipocyte-fatty acid binding protein (A-FABP) and high-sensitivity C-reactive protein (hsCRP) were measured in baseline samples. RESULTS: Seventy-six participants developed diabetes over 5.3 years (median). All five biomarkers significantly improved the log-likelihood of diabetes in a clinical diabetes prediction (CDP) model including age, sex, family history of diabetes, smoking, physical activity, hypertension, waist circumference, fasting glucose and dyslipidaemia. In ROC curve analysis, "adiponectin + TNF-α R2" improved the area under ROC curve (AUC) of the CDP model from 0.802 to 0.830 (P = 0.03), rendering its performance comparable to the "CDP + 2-hour post-OGTT glucose" model (AUC = 0.852, P = 0.30). A biomarker risk score, derived from the number of biomarkers predictive of diabetes (low adiponectin, high TNF-α R2), had similar performance when added to the CDP model (AUC = 0.829 [95% CI: 0.808-0.849]). CONCLUSIONS: The combined use of serum adiponectin and TNF-α R2 as biomarkers provided added value over traditional risk factors for diabetes prediction in Chinese and could be considered as an alternative to the OGTT.

Various pathways have been implicated in the pathogenesis of heart failure (HF) with preserved ejection fraction (HFPEF). Inflammation in response to comorbid conditions, such as hypertension and diabetes, may play a proportionally larger role in HFPEF as compared to HF with reduced ejection fraction (HFREF).This study investigated inflammation mediated by the tumor necrosis factor-alpha (TNFα) axis in community-based cohorts of HFPEF patients (n = 100), HFREF patients (n = 100) and healthy controls (n = 50). Enzyme-linked immunosorbent assays were used to investigate levels of TNFα, its two receptors (TNFR1 and TNFR2), and a non-TNFα cytokine, interleukin-6 (IL-6), in plasma derived from peripheral blood samples. Plasma levels of TNFα and TNFR1 were significantly elevated in HFPEF relative to controls, while levels of TNFR2 were significantly higher in HFPEF than both controls and HFREF. TNFα, TNFR1 and TNFR2 were each significantly associated with at least two of the following: age, estimated glomerular filtration rate, hypertension, diabetes, smoking, peripheral vascular disease or history of atrial fibrillation. TNFR2 levels were also significantly associated with increasing grade of diastolic dysfunction and severity of symptoms in HFPEF.Inflammation mediated through TNFα and its receptors, TNFR1 and TNFR2, may represent an important component of a comorbidity-induced inflammatory response that partially drives the pathophysiology of HFPEF.

Introduction: Density and co-expression of tumor necrosis factor (TNF) receptors may vary among cell populations. However, the role and potential of these changes remain unclear. This study aimed to determine the density of expression and co-expression of TNFR1/2 and the dose-dependent effect of soluble TNF on these parameters. Methods: Epithelial-like (HEp-2, K-562, MCF-7, ZR-75/1) and lymphoblast-like (MOLT-4, HL-60, Raji, RPMI-8226, IM-9) cell lines were characterized for co-expression of TNFR1/2 using a modified flow cytometry protocol. The dose-dependent effects of rhTNF on TNF receptor expression in these lines were studied. Results: This study reports a protocol for the simultaneous quantitative evaluation of the of TNF receptor number and co-expression of membrane-bound TNFR1/2. Cells within one tumor cell line were found to differ regarding their expression of type 1 and 2 TNFα receptors; simultaneously, cells with all 4 variants of co-expression may be present in culture. Conclusion: We demonstrated a dose-dependent effect of TNF on changes in the expression of TNFR1/2 by the percentage of positive cells and by the number of receptors, which may be used to control TNF-mediated processes in target cells. [ABSTRACT FROM AUTHOR]

Purpose: Tumor necrosis factor-alpha (TNF-α) is a proinflammatory cytokine that has been implicated in many aspects of the airway pathology in asthma. TNF-α blocking strategies are now being tried in asthma patients. This study investigated whether TNF-α blocking therapy inhibits airway inflammation and airway hyperresponsiveness (AHR) in a mouse model of asthma. We also evaluated the effect of TNF-α blocking therapy on cytokine production and adhesion molecule expression. Meterials and Methods: Ovalbumin (OVA) sensitized BALB/c female mice were exposed to intranasal OVA administration on days 31, 33, 35, and 37. Mice were treated intraperitoneally with soluble TNF-α receptor (sTNFR) during the OVA challenge. Results: There were statistically significant decreases in the numbers of total cell and eosinophil in bronchoalveolar lavage fluid (BALF) in the sTNFR treated group compared with the OVA group. However, sTNFR-treatment did not significantly decrease AHR. Anti-inflammatory effect of sTNFR was accompanied with reduction of T helper 2 cytokine levels including interleukin (IL)-4, IL-5 and IL-13 in BALF and vascular cell adhesion molecule 1 expression in lung tissue. Conclusion: These results suggest that sTNFR treatment can suppress the airway inflammation via regulation of Th2 cytokine production and adhesion molecule expression in bronchial asthma. [ABSTRACT FROM AUTHOR]

Pro-inflammatory conditions have long been associated with mammary carcinogenesis and breast cancer progression. The underlying mechanisms are incompletely understood but signaling of pro-inflammatory cytokine TNFα through its receptors TNFR1 and TNFR2 is a major mediator of inflammation in both obesity and in the response of tissues to radiation, 2 known risk factors for the development of breast cancer. Here, we demonstrated the loss of one TNFR2 allele led to ductal hyperplasia in the mammary gland with increased numbers of mammary epithelial stem cell and terminal end buds. Furthermore, loss of one TNFR2 allele increased the incidence of breast cancer in MMTV-Wnt1 mice and resulted in tumors with a more aggressive phenotype and metastatic potential. The underlying mechanisms include a preferential activation of canonical NF-κB signaling pathway and autocrine production of TNFα. Analysis of the TCGA dataset indicated inferior overall survival for patients with down-regulated TNFR2 expression. These findings unravel the imbalances in TNFR signaling promote the development and progression of breast cancer, indicating that selective agonists of TNFR2 could potentially modulate the risk for breast cancer in high-risk populations.