Levels Of Tumor Necrosis Factor Receptor Research Articles

The Regulatory Effect of Remifentanil on JNK Signaling during Remission of Flap Ischemia-Reperfusion Injury.

The impact of remifentanil on hypogastric flap function following ischemia-reperfusion (I/R) injury remains largely unknown, limiting its potential clinical application in flap surgery. This study investigated the therapeutic effects of remifentanil on hypogastric flap I/R injury. Aortic endothelial cells were extracted from the hypogastric flap I/R injury models established in-house using Sprague-Dawley rats, and were treated under hypoxic conditions. The cells were treated with 0.1, 1, 10 and 100 ng/mL remifentanil and 10 ng/mL anisomycin (the activator of c-Jun N-terminal kinase [JNK]). Histopathological changes and tumor necrosis factor alpha (TNF-α) content of the flaps were observed after hematoxylin-eosin staining and immunohistochemistry. Immunofluorescence, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) staining and flow cytometry were employed for apoptosis evaluation. Western blotting, quantitative real-time polymerase chain reaction (qRT-PCR) and enzyme-linked immunosorbent assay (ELISA) were utilized to assess the protein and gene expression levels of TNF receptor 1 (TNFR1), JNK1, phosphorylated (p)-JNK1, malondialdehyde (MDA), superoxide dismutase (SOD), nitric oxide (NO) and TNF-α in the flaps and cells. The endothelial necrosis and cell apoptosis of rat flaps induced by I/R injury were ameliorated by remifentanil, and declining aortic endothelial cell viability and augmented apoptosis induced by hypoxia were reversed by remifentanil (10, 100 ng/mL) (p < 0.05). Remifentanil reversed the increased expressions of TNFR1, JNK1, p-JNK1, MDA and TNF-α induced by I/R injury or hypoxia in the flaps and cells (p < 0.05), and counteracted the decreased levels of NO and SOD induced by I/R injury in the flaps (p < 0.05). Anisomycin reversed the effects of remifentanil on suppressing TNFR1, JNK1 and p-JNK1 levels and apoptosis in the cells (p < 0.05). Remifentanil ameliorates cell apoptosis and vascular endothelial necrosis induced by I/R injury in the hypogastric flap, likely by downregulating the TNF-α/TNFR1 pathway and JNK1 signaling. These findings suggest that remifentanil may be a promising therapeutic agent for improving hypogastric flap survival in clinical settings.

Simultaneous detection of multiple urinary biomarkers in patients with early-stage diabetic kidney disease using Luminex liquid suspension chip technology.

Several urinary biomarkers have good diagnostic value for diabetic kidney disease (DKD); however, the predictive value is limited with the use of single biomarkers. We investigated the clinical value of Luminex liquid suspension chip detection of several urinary biomarkers simultaneously. The study included 737 patients: 585 with diabetes mellitus (DM) and 152 with DKD. Propensity score matching (PSM) of demographic and medical characteristics identified a subset of 78 patients (DM = 39, DKD = 39). Two Luminex liquid suspension chips were used to detect 11 urinary biomarkers according to their molecular weight and concentration. The biomarkers, including cystatin C (CysC), nephrin, epidermal growth factor (EGF), kidney injury molecule-1 (KIM-1), retinol-binding protein4 (RBP4), α1-microglobulin (α1-MG), β2-microglobulin (β2-MG), vitamin D binding protein (VDBP), tissue inhibitor of metalloproteinases-1 (TIMP-1), tumor necrosis factor receptor-1 (TNFR-1), and tumor necrosis factor receptor-2 (TNFR-2) were compared in the DM and DKD groups. The diagnostic values of single biomarkers and various biomarker combinations for early diagnosis of DKD were assessed using receiver operating characteristic (ROC) curve analysis. Urinary levels of VDBP, RBP4, and KIM-1 were markedly higher in the DKD group than in the DM group (p < 0.05), whereas the TIMP-1, TNFR-1, TNFR-2, α1-MG, β2-MG, CysC, nephrin, and EGF levels were not significantly different between the groups. RBP4, KIM-1, TNFR-2, and VDBP reached p < 0.01 in univariate analysis and were entered into the final analysis. VDBP had the highest AUC (0.780, p < 0.01), followed by RBP4 (0.711, p < 0.01), KIM-1 (0.640, p = 0.044), and TNFR-2 (0.615, p = 0.081). However, a combination of these four urinary biomarkers had the highest AUC (0.812), with a sensitivity of 0.742 and a specificity of 0.760. The urinary levels of VDBP, RBP4, KIM-1, and TNFR-2 can be detected simultaneously using Luminex liquid suspension chip technology. The combination of these biomarkers, which reflect different mechanisms of kidney damage, had the highest diagnostic value for DKD. However, this finding should be explored further to understand the synergistic effects of these biomarkers.

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.

Exosome-associated mitochondrial DNA in late-life depression: Implications for cognitive decline in older adults

BackgroundDisrupted cellular communication, inflammatory responses and mitochondrial dysfunction are consistently observed in late-life depression (LLD). Exosomes (EXs) mediate cellular communication by transporting molecules, including mitochondrial DNA (EX-mtDNA), playing critical role in immunoregulation alongside tumor necrosis factor (TNF). Changes in EX-mtDNA are indicators of impaired mitochondrial function and might increase vulnerability to adverse health outcomes. Our study examined EX-mtDNA levels and integrity, exploring their associations with levels of TNF receptors I and II (TNFRI and TNFRII), and clinical outcomes in LLD. MethodsNinety older adults (50 LLD and 40 controls (HC)) participated in the study. Blood was collected and exosomes were isolated using size-exclusion chromatography. DNA was extracted and EX-mtDNA levels and deletion were assessed using qPCR. Plasma TNFRI and TNFRII levels were quantified by multiplex immunoassay. Correlation analysis explored relationships between EX-mtDNA, clinical outcomes, and inflammatory markers. ResultsAlthough no differences were observed in EX-mtDNA levels between groups, elevated levels correlated with poorer cognitive performance (r = −0.328, p = 0.002) and increased TNFRII levels (r = 0.367, p = 0.004). LLD exhibited higher deletion rates (F(83,1) = 4.402, p = 0.039), with a trend remaining after adjusting for covariates (p = 0.084). Deletion correlated with poorer cognitive performance (r = −0.335, p = 0.002). No other associations were found. LimitationCross-sectional study with a small number of participants from a specialized geriatric psychiatry treatment center. ConclusionOur findings suggest that EX-mtDNA holds promise as an indicator of cognitive outcomes in LLD. Additional research is needed to further comprehend the role of EX-mtDNA levels/integrity in LLD, paving the way for its clinical application in the future.

Continuous TNF-α exposure in mammary epithelial cells promotes cancer phenotype acquisition via EGFR/TNFR2 activation.

Tumor necrosis factor alpha (TNF-α), an abundant inflammatory cytokine in the tumor microenvironment (TME), is linked to breast cancer growth and metastasis. In this study, we established MCF10A cell lines incubated with TNF-α to investigate the effects of continuous TNF-α exposure on the phenotypic change of normal mammary epithelial cells. The established MCF10A-LE cell line, through long-term exposure to TNF-α, displayed cancer-like features, including increased proliferation, migration, and sustained survival signaling even in the absence of TNF-α stimulation. Unlike the short-term exposed cell line MCF10A-SE, MCF10A-LE exhibited elevated levels of epidermal growth factor receptor (EGFR) and subsequent TNF receptor 2 (TNFR2), and silencing of EGFR or TNFR2 suppressed the cancer-like phenotype of MCF10A-LE. Notably, we demonstrated that the elevated levels of NAD(P)H oxidase 4 (NOX4) and the resulting increase in reactive oxygen species (ROS) were associated with EGFR/TNFR2 elevation in MCF10A-LE. Furthermore, mammosphere-forming capacity and the expression of cancer stem cell (CSC) markers increased in MCF10A-LE. Silencing of EGFR reversed these effects, indicating the acquisition of CSC-like properties via EGFR signaling. In conclusion, our results reveal that continuous TNF-α exposure activates the EGFR/TNFR2 signaling pathway via the NOX4/ROS axis, promoting neoplastic changes in mammary epithelial cells within the inflammatory TME.

Circulating TNF receptor levels are associated with estimated glomerular filtration rate even in healthy individuals with normal kidney function

The association between serum tumor necrosis factor receptor (TNFRs: TNFR1, TNFR2) levels and estimated glomerular filtration rate (eGFR) observed in patients with diabetes has not been comprehensively tested in healthy subjects with normal kidney function. It also remains unclear whether TNFR levels differ by age and sex, and between healthy subjects and diabetics. We measured serum TNFR levels in 413 healthy subjects and 292 patients with type 2 diabetes. In healthy subjects, TNFR levels did not differ between men and women. Additionally, TNFR2, but not TNFR1, levels increased with age. In multivariate analysis, TNFR1 was associated only with cystatin C-based eGFR (eGFR-CysC), whereas TNFR2 was associated with systolic blood pressure in addition to eGFR-CysC. Both TNFRs were associated with lower eGFR (eGFR-Cys < 90 mL/min/1.73 m2) even after adjustment for relevant clinical factors. Upon combining healthy subjects and patients with diabetes, the presence of diabetes and elevated glycated hemoglobin level were significant factors in determining TNFR levels. TNFR levels were associated with eGFR-CysC, but were not affected by age and sex in healthy subjects with normal kidney function. TNFR levels in patients with diabetes appeared to be higher than in healthy subjects.

Effects of moxibustion on visceral hypersensitivity and colonic inflammatory response in mice with chronic ulcerative colitis.

To observe the effects of moxibustion at "Zusanli" (ST36) on the expression levels of tumor necrosis factor (TNF)-α, TNF receptor 1 (TNF-R1), p38 mitogen-activated protein kinase (P38 MAPK), and transient receptor potential vanilloid 1 (TRPV1) in the colon tissue of mice with chronic ulcerative colitis (UC), so as to explore the underlying mechanisms of moxibustion in improving visceral hypersensitivity in chronic UC. Male C57BL/6J mice were randomly divided into normal group, normal with moxibustion (NM) group, model group, and model with moxibustion (MM) group, with 10 mice in each group. The chronic UC model was established by drinking 2.5% dextran sodium sulfate for 3 cycles. Mice in the NM and MM groups received moxibustion at ST36 for 20 min, 5 days per week with a 2-day break, for a total of 4 weeks. The disease activity index (DAI) score of each group was evaluated before and after treatment. The minimum volume threshold of abdominal wall retraction reflex (AWR) was measured to observe the intestinal sensitivity of mice. The colon length was measured. The pathological changes of colon tissue were observed by HE staining. The expression of mucin in colon goblet cells was detected by periodate Scheff staining. The intestinal fibrosis was observed by Masson staining. The number of trypsin-positive cells (i.e., mast cell) and the expression level of TNF-α in colon tissue were detected by immunofluorescence staining. The expression levels of TNF-R1, P38 MAPK and TRPV1 in colon tissue were detected by immunohistochemistry. Compared with the normal group after treatment, the model group showed increased DAI score (P<0.001), decreased AWR minimum volume threshold (P<0.01), shortened colon length (P<0.001), significant inflammatory infiltration in the colon tissue, reduced mucin secretion (P<0.01), increased collagen fiber deposition (P<0.001), and elevated expression levels of TNF-α, TNF-R1, P38 MAPK, and TRPV1 (P<0.001, P<0.01, P<0.05). Compared with the model group, the MM group showed decreased DAI score (P<0.01), increased AWR minimum volume threshold (P<0.001), elongated colon length (P<0.001), reduced inflammatory cell infiltration, improved integrity of mucosal glandular structure, enhanced mucin secretion (P<0.01), decreased collagen fiber deposition (P<0.001), decreased number of mast cells in the colon tissue (P<0.001), and decreased expression levels of TNF-α, TNF-R1, P38 MAPK, and TRPV1 (P<0.001, P<0.01, P<0.05). There were no significant differences in the above index between the NM group and the normal group. Moxibustion can reduce visceral hypersensitivity, alleviate inflammatory infiltration and fibrotic damage in the colon tissue of mice with chronic UC. These effects may be associated with the down-regulation of TNF-α, TNF-R1, P38 MAPK, and TRPV1 expression in colon.

The rs11684747 and rs55790676 SNPs of ADAM17 influence tuberculosis susceptibility and plasma levels of TNF, TNFR1, and TNFR2.

The proteolytic activity of A Disintegrin and Metalloproteinase 17 (ADAM17) regulates the release of tumor necrosis factor (TNF) and TNF receptors (TNFRs) from cell surfaces. These molecules play important roles in tuberculosis (TB) shaping innate immune reactions and granuloma formation. Here, we investigated whether single nucleotide polymorphisms (SNPs) of ADAM17 influence TNF and TNFRs levels in 224 patients with active TB (ATB) and 118 healthy close contacts. Also, we looked for significant associations between SNPs of ADAM17 and ATB status. TNF, TNFR1, and TNFR2 levels were measured in plasma samples by ELISA. Four SNPs of ADAM17 (rs12692386, rs1524668, rs11684747, and rs55790676) were analyzed in DNA isolated from peripheral blood leucocytes. The association between ATB status, genotype, and cytokines was analyzed by multiple regression models. Our results showed a higher frequency of rs11684747 and rs55790676 in close contacts than ATB patients. Coincidentally, heterozygous to these SNPs of ADAM17 showed higher plasma levels of TNF compared to homozygous to their respective ancestral alleles. Strikingly, the levels of TNF and TNFRs distinguished participant groups, with ATB patients displaying lower TNF and higher TNFR1/TNFR2 levels compared to their close contacts. These findings suggest a role for SNPs of ADAM17 in genetic susceptibility to ATB.

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.

Levels of soluble TNF receptors (sTNFR1 and sTNFR2) increase with clinical worsening of patients and are related to COVID-19 mortality

The present study aimed to inspect the serum levels of the soluble receptors, sTNFR1 and sTNFR2, in patients with COVID-19. The large production of inflammatory cytokines is an essential process in the pathogenesis of COVID-19. TNF is a multifaceted proinflammatory cytokine which has soluble and membrane receptors. Thus, knowing the role of these receptors will help better understand this disease's immunopathogenesis. We included 131 patients confirmed for SARS-CoV-2, separated into three groups: ward patients without O2 support, group A (n = 14); ward patients with O2 support, group B (n = 85), and patients in an intensive care unit (ICU), group C (n = 32), making up the receptors dosed by flow cytometry. The results showed that sTNFR1 and sTNFR2 are associated with disease severity, being higher in group C when compared to group A. As for the levels of receptors and their relationship with the degree of lung involvement, we found higher values of sTNFR1 in patients in group 1 (pulmonary involvement < 25%), suggesting that inflammatory processes related to TNF are not necessarily associated with the primary site of infection. When we analysed the patients who passed away compared to those who recovered, both receptors significantly increased the mortality numbers. These findings suggest a relevant influence of soluble receptors in the inflammatory processes involved in the pathogenesis of COVID-19. Wherefore, we suggest using these receptors as biomarkers of severity and mortality of the disease.

Plasma Biomarkers and Incident CKD Among Individuals Without Diabetes

Biomarkers of kidney disease progression have been identified in individuals with diabetes and underlying chronic kidney disease (CKD). Whether or not these markers are associated with the development of CKD in a general population without diabetes or CKD is not well established. Prospective observational cohort. In the Atherosclerosis Risk in Communities) study, 948 participants were studied. The baseline plasma biomarkers of kidney injury molecule-1 (KIM-1), monocyte chemoattractant protein-1 (MCP-1), soluble urokinase plasminogen activator receptor (suPAR), tumor necrosis factor receptor 1 (TNFR-1), tumor necrosis factor receptor 2 (TNFR-2), and human cartilage glycoprotein-39 (YKL-40) measured in 1996-1998. Incident CKD after 15 years of follow-up defined as≥40% estimated glomerular filtration rate decline to<60mL/min/1.73m2 or dialysis dependence through United States Renal Data System linkage. Logistic regression and C statistics. There were 523 cases of incident CKD. Compared with a random sample of 425 controls, there were greater odds of incident CKD per 2-fold higher concentration of KIM-1 (OR, 1.49; 95% CI, 1.25-1.78), suPAR (OR, 2.57; 95% CI, 1.74-3.84), TNFR-1 (OR, 2.20; 95% CI, 1.58-3.09), TNFR-2 (OR, 2.03; 95% CI, 1.37-3.04). After adjustment for all biomarkers, KIM-1 (OR, 1.42; 95% CI, 1.19-1.71), and suPAR (OR, 1.86; 95% CI, 1.18-2.92) remained associated with incident CKD. Compared with traditional risk factors, the addition of all 6 biomarkers improved the C statistic from 0.695-0.731 (P<0.01) and using the observed risk of 12% for incident CKD, the predicted risk gradient changed from 5%-40% (for the 1st-5th quintile) to 4%-44%. Biomarkers and creatinine were measured at one time point. Higher levels of KIM-1, suPAR, TNFR-1, and TNFR-2 were associated with higher odds of incident CKD among individuals without diabetes. For people with diabetes or kidney disease, several biomarkers have been shown to be associated with worsening kidney disease. Whether these biomarkers have prognostic significance in people without diabetes or kidney disease is less studied. Using the Atherosclerosis Risk in Communities study, we followed individuals without diabetes or kidney disease for an average of 15 years after biomarker measurement to see if these biomarkers were associated with the development of kidney disease. We found that elevated levels of KIM-1, suPAR, TNFR-1, and TNFR-2 were associated with the development of kidney disease. These biomarkers may help identify individuals who would benefit from interventions to prevent the development of kidney disease.

Selective Inhibition of Soluble Tumor Necrosis Factor Alters the Neuroinflammatory Response following Moderate Spinal Cord Injury in Mice.

Clinical and animal model studies have implicated inflammation and glial and peripheral immune cell responses in the pathophysiology of spinal cord injury (SCI). A key player in the inflammatory response after SCI is the pleiotropic cytokine tumor necrosis factor (TNF), which exists both in both a transmembrane (tmTNF) and a soluble (solTNF) form. In the present study, we extend our previous findings of a therapeutic effect of topically blocking solTNF signaling after SCI for three consecutive days on lesion size and functional outcome to study the effect on spatio-temporal changes in the inflammatory response after SCI in mice treated with the selective solTNF inhibitor XPro1595 and compared to saline-treated mice. We found that despite comparable TNF and TNF receptor levels between XPro1595- and saline-treated mice, XPro1595 transiently decreased pro-inflammatory interleukin (IL)-1β and IL-6 levels and increased pro-regenerative IL-10 levels in the acute phase after SCI. This was complemented by a decrease in the number of infiltrated leukocytes (macrophages and neutrophils) in the lesioned area of the spinal cord and an increase in the number of microglia in the peri-lesion area 14 days after SCI, followed by a decrease in microglial activation in the peri-lesion area 21 days after SCI. This translated into increased myelin preservation and improved functional outcomes in XPro1595-treated mice 35 days after SCI. Collectively, our data suggest that selective targeting of solTNF time-dependently modulates the neuroinflammatory response by favoring a pro-regenerative environment in the lesioned spinal cord, leading to improved functional outcomes.

TNFR2 as a Potential Biomarker for Early Detection and Progression of CKD

The inflammatory pathway driven by TNF-α, through its receptors TNFR1 and TNFR2, is a common feature in the pathogenesis of chronic kidney disease (CKD), regardless of the initial disease cause. Evidence correlates the chronic inflammatory status with decreased renal function. Our aim was to evaluate the potential of TNF receptors as biomarkers for CKD diagnosis and staging, as well as their association with the progression of renal lesions, in rat models of early and moderate CKD. We analyzed the circulating levels of inflammatory molecules-tumor necrosis factor-alpha (TNF-α), tumor necrosis factor receptor 1 (TNFR1) and 2 (TNFR2) and tissue inhibitor of metalloproteinase-1 (TIMP-1)-and studied their associations with TNFR1 and TNFR2 renal expression, glomerular and tubulointerstitial lesions, and with biomarkers of renal (dys)function. An increase in all inflammatory markers was observed in moderate CKD, as compared to controls, but only circulating levels of both TNFR1 and TNFR2 were significantly increased in the early disease; TNFR2 serum levels were negatively correlated with eGFR. However, only TNFR2 renal expression increased with CKD severity and showed correlations with the score of mild and advanced tubular lesions. Our findings suggest that renal TNFR2 plays a role in CKD development, and has potential to be used as a biomarker for the early detection and progression of the disease. Still, the potential value of this biomarker in disease progression warrants further investigation.

Effects of the water-soluble fraction of diesel oil on the sera biochemical indicators, histological changes, and immune responses of black rockfish Sebastes schlegelii

In order to understand the physiological and immune responses of Sebastes schlegelii to the water-soluble fraction of diesel oil (WSD), S. schlegelii were used as the experimental objects to study the effect of WSD on the sera biochemical indicators, histological changes, and immune responses. Significant differences in sera biochemical indicators were observed in S. schlegelii after WSD exposure. The alkaline phosphatase (ALP), glucose (GLU), and globulin (GLB) were reduced by 3.51-fold, 3.12- fold, and 1.58-fold, respectively; however, K+ was increased by 3.55-fold. The results of HE staining showed that interstitial congestion was observed in the liver; the secondary lamellae deformity and hyperplasia, epithelial lifting, the primary lamellae hyperplasia, and aneurism were observed in the gill. Epidermis thickness increased, and epidermal hyperplasia in the skin was shown. The length of the secondary lamellae shortened significantly after WSD exposure. The results of AB-PAS staining showed that three different types of mucous cells were observed in the gill, and a significant increase in the number of all three types of mucous cells was observed after WSD exposure (P < 0.05). In addition, the results of the relative mRNA expressions in the liver of eleven immune-related genes showed that the relative expression levels of IL-1β, IL-8, TNF receptor, BAFF, C1s, C1r, and MyD88 in the WSD group were substantially higher than those in the LPS group (P < 0.05), and the relative expression of caspase 10 was significantly lower than that in the LPS group (P < 0.05). At the same time, no significant differences were observed in the relative expression levels of IL-1, TNFα, and C1inh between the two groups (P > 0.05). This study was expected to provide essential data for health assessments of S. schlegelii and establish the foundation for the immune-related researches of S. schlegelii after WSD exposure.

Investigating the renoprotective effect of C21 in male mice with sepsis via modulation of p-AKT/PI3K expression

This study aimed to investigate if C21 could prevent acute renal injury induced by sepsis by regulating the expression of p-AKT/PI3K. Five equal groups of 25 adult male Swiss-albino mice were randomly divided (n=5): sham (laparotomy without CLP), CLP, vehicle (equivalent amount of DMSO one hour before CLP), and C21 (0.03 mg/kg, one hour before CLP). ELISA was used to measure serum inflammatory mediators, and the expression of PI3K and P-AKT was determined using PCR and immunohistochemistry (IHC), respectively. TNF, TNF receptor, F8-isoprostane, urea, creatinine, and IL-6 blood levels were considerably lower in the CLP group (p<0.05) compared to the sham group, whereas the C21 treated group had significantly (p<0.05) greater levels of these inflammatory mediators. The IHC analysis revealed that P-AKT expression was significantly lower (p<0.05) in the CLP group compared to the sham group, while the C21 pretreatment group had significantly higher levels of P-AKT expression compared to the CLP group (p<0.05). The PI3K expression in the CLP group was significantly lower than in the sham group (p<0.05), according to PCR results, whereas the PI3K expression in the C21 pretreatment group was significantly greater than in the CLP group (p<0.05). This study showed that C21 might reduce levels of pro-inflammatory cytokines, including TNF-, IL-6, and TNF receptor, by modulating the PI3K/AKT signaling pathways, which can, in turn, reduce renal dysfunction during CLP-induced sepsis in male mice.

Genetically proxied inhibition of tumor necrosis factor and the risk of colorectal cancer: A drug-target mendelian randomization study.

Background: Previous studies suggested that anti-TNF drugs might be repurposed as a preventive treatment for colorectal cancer. We aimed to examine whether genetically proxied inhibition of tumor necrosis factor receptor 1 (TNFR1) reduces the absolute risk of colorectal cancer through mendelian randomization (MR) analysis. Methods: We obtained 28 single nucleotide polymorphisms (SNPs) that were located within a ±15 kilobase window of the TNFRSF1A-the gene that encodes the TNFR1 protein, and we used genetic data from three GWAS studies of circulating levels of TNFR1, C-reactive protein (CRP), and white blood counts (WBC) to screen SNPs that proxied the inhibition of TNFR1. Positive control analyses were then performed by using another three GWAS data from the ulcerative colitis cohort (n = 45,975), Crohn's disease cohort (n = 40,266), and multiple sclerosis cohort (n = 115,803) to confirm the effect of the included SNPs. A two-sample mendelian randomization analysis was performed to examine the association between TNFR1 inhibition and the absolute risk reduction (ARR) of colorectal cancer. Results: We finally included seven SNPs to proxy the anti-TNF effect, and these SNPs caused lower levels of TNFR1, CRP, and white blood counts. In positive control analyses, the included SNPs caused lower odds ratio of ulcerative colitis and Crohn's disease but a higher odds ratio of multiple sclerosis, consistent with drug mechanistic actions and previous trial evidence. By using the inverse-variance weighted analyses to combine the effects of the seven SNPs, we found that the anti-TNF effect was associated with a 0.988 (95%CI 0.985-0.991) mg/L decrease in CRP levels and a reduction in the risk of colorectal cancer (absolute risk reduction -2.1%, 95%CI -3.8% to -0.4%, p = 0.01). Conclusion: Our study confirmed that anti-TNF drugs were associated with a risk reduction in colorectal cancer. Physicians could consider using anti-TNF drugs for the prevention of colorectal cancer, especially in patients with high risks of developing cancer.

Levels of TNF-α and Soluble TNF Receptors in Normal-Weight, Overweight and Obese Patients with Dilated Non-Ischemic Cardiomyopathy: Does Anti-TNF Therapy Still Have Potential to Be Used in Heart Failure Depending on BMI?

We sought to measure the levels of adipokines, TNF-α and soluble receptors (sTNFr1, sTNFr2) in heart failure patients with reduced ejection fraction (HFrEF) due to non-ischemic cardiomyopathy (nDCM). A total of 123 patients with HFrEF due to nDCM were divided into three groups according to BMI: 34 (27.6%) normal weight, 56 (45.5%) overweight and 33 (26.8%) obese. A six-minute walk test, echocardiography and right heart catheterization were performed. Serum concentrations of adiponectin, leptin, NT-proBNP, blood hemoglobin, sodium, creatinine, ALAT, AspAT, bilirubin, CRP, lipids, TNF-α, sTNFr1 and sTNFr2 receptors were measured. Obese patients had the lowest NT-proBNP concentrations, significantly higher leptin levels and higher leptin/adiponectin ratios. The concentration of sTNFr1 was higher in normal-weight patients. In all groups, TNF-α concentrations correlated positively with sTNFr1 (p &lt; 0.001). Higher levels of sTNFr1 were associated with higher sTNFr2 (p &lt; 0.001) and CRP (p &lt; 0.001). Moreover, the concentration of sTNFr2 positively correlated with CRP (p &lt; 0.05) and adiponectin (p &lt; 0.001). Levels of TNF-α were not associated with elevated CRP. This study demonstrated that changes in the concentrations of TNF and its receptors differ between groups of patients with different BMI. These findings suggest that the effective use of anti-TNF therapy is dependent not only on BMI, but also on concentrations of TNF-α receptors and other laboratory parameters.

A TNFR1–UBCH10 axis drives lung squamous cell carcinoma dedifferentiation and metastasis through a cell-autonomous signaling loop

Tumor necrosis factor receptor 1 (TNFR1), encoded by TNFRSF1A, is a critical transducer of inflammatory pathways, but its physiological role in human cancer is not completely understood. Here, we observed high expression of TNFR1 in many human lung squamous cell carcinoma (SCCs) samples and in spontaneous lung SCCs derived from kinase-dead Ikkα knock-in (KA/KA) mice. Knocking out Tnfrf1a in KA/KA mice blocked lung SCC formation. When injected via tail vein, KALLU+ lung SCC cells that highly expressed TNFR1/TNF, Sox2, c-Myc, Twist1, Bcl2, and UBCH10, generated dedifferentiated spindle cell carcinomas with epithelial–mesenchymal transition markers in mouse lungs. In contrast, KALLU+ cells with silenced TNFR1 and KALLU- cells that expressed low levels of TNFR1 generated well-differentiated lung SCCs and were less tumorigenic and metastatic. We identified a downstream effector of TNFR1: oncogenic UBCH10, an E2 ubiquitin-conjugating enzyme with targets including Twist1, c-Myc, and Sox2, which enhanced SCC cell dedifferentiation. Furthermore, Tg-K5.TNFR1;KA/KA mice, which expressed transgenic TNFR1 in keratin 5-positve epithelial cells, developed more poorly differentiated and metastatic lung SCCs than those found in KA/KA mice. These findings demonstrate that an overexpressed TNFR1–UBCH10 axis advances lung carcinogenesis and metastasis through a dedifferentiation mechanism. Constituents in this pathway may contribute to the development of differentiation-related therapies for lung SCC.

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.

The utility of inflammatory and endothelial factors in the prognosis of severe dengue

BackgroundSevere dengue is associated with a considerable risk of mortality, and there is currently a lack of appropriate prognostic biomarkers to predict its severity. Pathogenesis of severe dengue is characterized by overt inflammation, endothelial activation, and increased vascular permeability. The current study investigates the utility of endothelial, inflammatory, and vascular permeability factors as biomarkers to identify dengue severity, which could improve disease prognosis and management. MethodsThe dengue-positive subjects were classified based on seropositivity for NS1, IgM, and IgG. The samples in each group were quantified for basic clinical investigations. The levels of Interleukin-6 (IL-6), Tumor necrosis factor receptor 1 (TNFR1), EOTAXIN, Monocyte chemoattractant protein-1 (MCP-1), Monokine induced by interferon-gamma (MIG), Intercellular adhesion molecule-1 (ICAM-1), Vascular cell adhesion molecule-1 (VCAM-1), Thrombomodulin, and Angiopoietin-2 were estimated in all serum samples using the multiplex bead-based assay. ResultsIgG seropositive dengue patients showed abnormal laboratory characteristics and severe dengue symptoms. Among the studied markers, only IL-6, TNFR1, ICAM-1, VCAM-1, Thrombomodulin, and Angiopoietin-2 were significantly elevated in IgG seropositive patients compared to healthy controls. Increased IL-6 and TNFR1 levels were associated with decreased platelet count and elevated Hematocrit levels in IgG seropositive patients. Furthermore, ROC curve analysis indicated that IL-6, TNFR1, Thrombomodulin, and Angiopoietin-2 showed good potential for predicting dengue severity. ConclusionInflammatory markers IL-6 and TNFR1, and endothelial factors Angiopoietin-2 and Thrombomodulin, could serve as prognostic markers for severe dengue. These findings also encourage the future study of these biomarkers in the pathogenesis of severe dengue infection.