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Introduction: Large-scale clinical trials of sodium-glucose cotransporter 2 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. Methods: Patients with type 2 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 4 months. 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 month 4 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. Results: Participants (n = 123) had a mean age of 64.1 years (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 19.2 mg/gCr (IQR 7.1–48.7) to 13.3 mg/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). Conclusion: After the 4-month SGLT2i administration, decreased albuminuria level was associated with decreased serum TNFR level in patients with T2DM. Trial Registration Number: UMIN000031947. Plain Language Summary: Previous studies have demonstrated the synergistic proteinuria-reducing effect of sodium-glucose cotransporter 2 inhibitors (SGLT2i) in combination therapy with renin–angiotensin system blockers; however, the underlying mechanisms of this effect are poorly understood. This study was based on our hypothesis that the proteinuria-reducing effect is associated with the anti-inflammatory effects of SGLT2i beyond the effect on glycemic control. In total, 123 patients with type 2 diabetes mellitus (T2DM) were administered the recommended daily dose of SGLT2i for 4 months. 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) as markers of glomerular and proximal tubular damage at 4 months from the baseline. Secondary outcomes included changes in kidney injury biomarkers, inflammation, and oxidative stress to examine the effects of treatment on the kidneys. 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. We found that administration of SGLT2i decreased the urine albumin-to-creatinine ratio but did not affect the urine liver-type fatty acid-binding protein-to-creatinine ratio. Further, SGLT2i may exert a proteinuria-reducing effect dependent on the anti-inflammatory effect in patients with T2DM. The inflammation-reducing and renoprotective mechanisms of SGLT2i remain to be fully clarified, but this study provides novel evidence regarding the mechanism. The study findings can help in developing anti-inflammatory agents for metabolic diseases. [ABSTRACT FROM AUTHOR]

Increasing evidence suggests that cytokines and chemokines play crucial roles in chronic itch. In the present study, we evaluated the roles of tumor necrosis factor-alpha (TNF-α) and its receptors TNF receptor subtype-1 (TNFR1) and TNFR2 in acute and chronic itch in mice. Compared to wild-type (WT) mice, TNFR1-knockout (TNFR1-KO) and TNFR1/R2 double-KO (DKO), but not TNFR2-KO mice, exhibited reduced acute itch induced by compound 48/80 and chloroquine (CQ). Application of the TNF-synthesis inhibitor thalidomide and the TNF-α antagonist etanercept dose-dependently suppressed acute itch. Intradermal injection of TNF-α was not sufficient to evoke scratching, but potentiated itch induced by compound 48/80, but not CQ. In addition, compound 48/80 induced TNF-α mRNA expression in the skin, while CQ induced its expression in the dorsal root ganglia (DRG) and spinal cord. Furthermore, chronic itch induced by dry skin was reduced by administration of thalidomide and etanercept and in TNFR1/R2 DKO mice. Dry skin induced TNF-α expression in the skin, DRG, and spinal cord and TNFR1 expression only in the spinal cord. Thus, our findings suggest that TNF-α/TNFR1 signaling is required for the full expression of acute and chronic itch via peripheral and central mechanisms, and targeting TNFR1 may be beneficial for chronic itch treatment. [ABSTRACT FROM AUTHOR]

Identification of bioactive compounds directly from complex herbal extracts is a key issue in the study of Chinese herbs. The present study describes the establishment and application of a sensitive, efficient, and convenient method based on surface plasmon resonance (SPR) biosensors for screening active ingredients targeting tumor necrosis factor receptor type 1 (TNF-R1) from Chinese herbs. Concentration-adjusted herbal extracts were subjected to SPR binding assay, and a remarkable response signal was observed in Rheum officinale extract. Then, the TNF-R1-bound ingredients were recovered, enriched, and analyzed by UPLC-QTOF/MS. As a result, physcion-8-O-β- d-monoglucoside (PMG) was identified as a bioactive compound, and the affinity constant of PMG to TNF-R1 was determined by SPR affinity analysis ( K = 376 nM). Pharmacological assays revealed that PMG inhibited TNF-α-induced cytotoxicity and apoptosis in L929 cells via TNF-R1. Although PMG was a trace component in the chemical constituents of the R. officinale extract, it had considerable anti-inflammatory activities. It was found for the first time that PMG was a ligand for TNF receptor from herbal medicines. The proposed SPR-based screening method may prove to be an effective solution to analyzing bioactive components of Chinese herbs and other complex drug systems. [Figure not available: see fulltext.] [ABSTRACT FROM AUTHOR]

Soluble human tumor necrosis factor receptors (shTNFRI and shTNFRII) are antagonists of tumor necrosis factor-α (TNF-α) and are under clinical investigation as therapy for autoimmune diseases and transplant rejection. However, shTNFRI and shTNFRII are limited for clinical usage because of their short half-lives in vivo. Recombinant TNF-α receptors (infliximab and etanercept) are used in treatment of rheumatoid arthritis and Crohn's disease but are also being tested for a number of other autoimmune diseases. Human serum albumin (HSA) has been used to construct long-acting fusion proteins. Here, we report the effect of fusion of HSA with shTNFRI and with shTNFRII on shTNFR's neutralizing activity against TNF-α. HSA fusion proteins were separately expressed in Pichia pastoris. Purified recombinant shTNFRI-HSA, HSA-shTNFRI and HSA-shTNFRII could block the cytolytic activity of TNF-α in L929 cells, and the fusion at N-terminus of shTNFRI could result in larger degree of activity decline than that at the C-terminus. Activity of three fusion proteins was much weaker than etanercept, which demonstrated that fusion of HSA significantly influenced TNF-α neutralizing activity of shTNFRs. Compared with Fc fragment, HSA fusion technology may therefore not be an ideal strategy in development of long-acting shTNFRs protein drugs. [ABSTRACT FROM AUTHOR]

Frontotemporal lobar dementia (FTLD) is the most common cause of dementia in patients younger than 60 years of age, and causes progressive neurodegeneration of the frontal and temporal lobes usually accompanied by devastating changes in language or behavior in affected individuals. Mutations in the progranulin ( GRN) gene account for a significant fraction of familial FTLD, and in the vast majority of cases, these mutations lead to reduced expression of progranulin via nonsense-mediated mRNA decay. Progranulin is a secreted glycoprotein that regulates a diverse range of cellular functions including cell proliferation, cell migration, and inflammation. Recent fundamental discoveries about progranulin biology, including the findings that sortilin and tumor necrosis factor receptor (TNFR) are high affinity progranulin receptors, are beginning to shed light on the mechanism(s) by which progranulin deficiency causes FTLD. This review will explore how alterations in basic cellular functions due to PGRN deficiency, both intrinsic and extrinsic to neurons, might lead to the development of FTLD. [ABSTRACT FROM AUTHOR]

Aim:To investigate the population pharmacokinetics of recombinant human tumor necrosis factor receptor-Fc fusion protein (rhTNFR-Fc) administered via subcutaneous (SC) injection in healthy Chinese volunteers and in Chinese patients with ankylosing spondylitis (AS).Methods:Thirty-two healthy volunteers were randomly assigned to receive a single SC injection of 12.5, 25, 37.5, or 50 mg of rhTNFR-Fc. Twenty male patients with moderate AS were randomly assigned to receive seven consecutive SC injections of rhTNFR-Fc at either 25 mg twice a week (BIW) or 50 mg once a week (QW). Population pharmacokinetic (PK) analysis was applied to obtain PK parameters of rhTNFR-Fc by the NONMEM method.Results:The data were best described by a one-compartment model with lag time. We found that gender had a significant effect on the apparent clearance (CL/F), with the male CL/F ratio being only 0.665 times the female ratio; the absorption coefficient (F) of multiple dosages of rhTNFR-Fc was only 0.674 times that of a single dosage. The outcome parameters were CL/F (female: 0.168 L/h, male: 0.110 L/h), the apparent volume of distribution (Vd/F: 15.5 L), the absorption rate constant (Ka) (single dosage: 0.0605 h−1, multiple dosage: 0.0408 h−1), and the lag time (Tlag: 1.03 h). The inter-individual variability in the CL/F, Vd/F, Ka, and Tlag were 33.3%, 42.7%, 55.6%, and 81.8%, respectively.Conclusion:Chinese females have a higher CL/F than Chinese males, and multiple dosings can significantly decrease the absorption of rhTNFR-Fc (SC). The population PK parameters of rhTNFR-Fc in healthy Chinese volunteers and patients with AS were similar to those reported for subjects in published American studies. [ABSTRACT FROM AUTHOR]

Effector cells play a crucial role in the immune system of higher vertebrates in eliminating invading pathogens and transformed cells that could cause disease or death of the individual. To be effective and specific, immune responses have to distinguish between self and nonself. Mechanisms of central and peripheral tolerance have evolved to control effector cells that could respond to autoantigens. Regulatory T-cells (Treg cells) are critical modulators of effector cells in the periphery that suppress autoreactive T-cells but are also involved in modulating immune responses against invading pathogens. Identification of surface markers of Treg cells and the development of in vitro systems to study the suppressive function of Treg cells have revealed distinct phenotypic and functional subsets of Treg cells. Several tumor necrosis factor receptor (TNFR) family members have been shown to play a role in the development, homeostasis, and suppressor function of Treg cells. Recent findings suggest that TNFRs and other cell-surface molecules of Treg cells can be explored for therapeutic strategies targeting autoimmune disorders, cancer, and immune responses against pathogens. [ABSTRACT FROM AUTHOR]

Narcolepsy is a debilitating sleep disorder characterized by daytime sleepiness and cataplexy. The strong association of narcolepsy with the HLA system suggests an autoimmune cause. Tumor necrosis factor is a cytokine involved in both regulation of immune mechanisms and sleep. Several studies were undertaken to determine a contribution of tumor necrosis factor and its receptors to the pathogenesis of narcolepsy. A significant increase in the 196R allele, a functionally relevant polymorphism in the TNFR2 gene, has been found in Japanese patients, indicating altered transduction of tumor necrosis factor signals. Here we explore polymorphisms in both tumor necrosis factor receptor genes as risk factors in a German population sample. Neither the polymorphism in the TNFR1 nor that in the TNFR2 gene was associated with narcolepsy. Our findings contrast to those previously published and thus provide evidence for genetic heterogeneity between different narcolepsy populations. [ABSTRACT FROM AUTHOR]

Objective:We assessed the presence of tumor necrosis factor receptor-1 (TNF-R1), apoptosis, and simultaneous expression of 92-kDa collagenase type IV (MMP-9) in samples of human chorioamnion from women with premature rupture of membranes (PROM).Methods:Amniotic membranes from women who underwent normal labor, cesarean delivery, or had PROM at term were studied by immunohistochemistry for localization of TNF-R1 and R2. Transmission electron microscopy and DNA fragmentation analyses by agarose gel electrophoresis were performed to identify apoptosis characteristics. Zymography and in situ zymography were used to assess gelatinolytic activity.Results:We found that TNF-R1 was abundant in membranes from subjects who had normal labor and very abundant in those who had PROM. By contrast TNF-R2 was abundant only in membranes from subjects who had cesarean delivery. Gelatinolytic activity was associated with extracellular matrix rather than cells and was higher in extracts from fetal membranes from PROM and normal labor than in extracts obtained from cesarean deliveries. Transmission electron microscopy of fetal membranes from PROM revealed ultrastructural characteristics in amnion epithelium consistent with type II apoptosis. DNA laddering in agarose gel electrophoresis corroborated results from DNA fragmentation.Conclusion:During PROM the fetal membranes undergo type II apoptosis and extracellular matrix degradation in association with TNF-R1 expression. [ABSTRACT FROM PUBLISHER]

Tumor necrosis factor (TNF)-α has been implicated in pathophysiological processes in coronary artery disease (CAD). TNF receptor 2 is of particular interest in mediating such effects. The gene for this receptor (TNFRSF1B) has, moreover, been implicated in hypertension, elevated cholesterol and insulin resistance. TNFRSF1B is thus a worthy candidate in studies of the genetic basis of CAD. We therefore conducted a case-control study of a microsatellite marker with five alleles (CA13-CA17) in intron 4 of TNFRSF1B in 1006 well-characterized white patients with angiographically confirmed CAD and a control group of 183 healthy subjects. We found a strong association of the TNFRSF1B marker with CAD (χ2=40, P=0.00000069). The frequency of the CA16 allele was 33% in CAD vs. 21% in control (odds ratio, OR, to have CAD for presence vs. absence of CA16 allele in CA16 homozygotes was 4.5, 95% CI 2.1–9.4, P<0.0001; in CA16 heterozygotes or was 1.3, 95% CI 0.94–1.89, P=0.10). The frequency of the major allele (CA15) was 43% in CAD vs. 56% in controls (in CA15 homozygotes OR 0.33, 95% CI 0.20–0.52, P<0.0001; in heterozygotes OR 0.41, 95% CI 0.26–0.63, P<0.0001). In a stepwise logistic regression model the CA16 allele was significantly associated with overweight (OR 1.44, 95% CI 1.0–1.9, P=0.027). Apolipoprotein A-I was elevated (P<0.0001), as was high-density lipoprotein (P=0.098), and severity of angina was decreased (P=0.024) as a function of genotype. Plasma soluble (s) TNF-R2 was 5.1±0.1 ng/ml in CAD vs. 3.2±0.1 in control (P<0.0001), 5.2±0.1 in the presence vs. 4.6±0.2 in the absence of vessel disease (P=0.009), and rose with increasing severity of angina: 4.2±0.2 (no angina), 5.0±0.1 (stable angina), 5.4±0.2 (unstable angina; P=0.003). sTNF-R2 was correlated with age, cholesterol, creatinine, fibrinogen, transforming growth factor β and homocysteine and was influenced by TNFRSF1B genotype. Thus genetic variation in or near the TNFRSF1B locus may predispose to CAD. [ABSTRACT FROM AUTHOR]

Tumor necrosis factor-α (TNF-α) has been found to be elevated in patients during hemodialysis and is thought to mediate some of the immune and metabolic dysfunctions in these patients. It has been speculated that infusions of soluble TNF receptor (sTNF-R) may prevent some of the cytotoxic effects of TNF. However, little is still known about preexisting serum TNF-R levels in patients with chronic renal failure, with or without hemodialysis. Therefore we analyzed serum samples of sTNF-R in 26 patients with chronic renal failure (group I), 6I hemodialysis patients (group II), 9 renal transplant recipients with acute renal failure requiring posttransplant dialysis (group III), 13 renal transplant patients with rejection and moderate kidney dysfunction (group IV), and 21 renal transplant recipients with borderline kidney dysfunction and diverse infectious complications (group V). Control groups consisted of 34 blood donors and diseased controls (11 renal transplant recipients with normal kidney function without complications). All patient groups showed significantly higher sTNF-R levels compared to the control groups. In groups I, IV, and V comparable levels were observed. In group I there was a clear correlation between sTNF-R levels and serum creatinine. The highest sTNF-R serum levels were seen in groups II and III, but there was no correlation with creatinine. In the posttransplant cases (group III and diseased controls) there was a decrease in sTNF-R with improvement of kidney function. These data strongly suggest that sTNF-R serum levels are dependent on kidney function. [ABSTRACT FROM AUTHOR]

Increased serum levels of soluble tumor necrosis factor receptors (TNFRs) have been observed in patients with various types of malignancies. For the monitoring of ovarian cancer during treatment serum TNFRs have given information equivalent or better than that obtained by CA 125. In this study, we compared the diagnostic value of TNFRs and CA 125 in discriminating ovarian cancer from benign pelvic masses. Preoperative serum levels of p55 and p75, two distinct types of TNFRs, and that of CA 125 were determined by immunoassays in 45 patients with malignant and 27 patients with benign tumors operated consecutively. A group of 26 healthy women served as controls. For each of the three markers the group with ovarian cancer showed significantly higher values than the group with benign masses (p < 0.01). The rate of marker elevation correlated with ovarian cancer staging. Using upper cutoff levels of 2.0 ng/ml (p55), 4.3 ng/ml (p75) and 20 U/ml (CA 125), the calculated sensitivities were 58% (p55), 16% (p75) and 82% (CA 125). The specificities were 89% (p55), 96% (p75) and 85% (CA 125), respectively. Adding p55 to CA 125 did not increase the diagnostic values compared to using the CA 125 test alone. Our data confirm the superiority of serum CA 125 as a marker for discriminating ovarian cancer from benign pelvic masses. The p75 marker was found to be of no value, and for the detection of early stage ovarian cancer the sensitivity of p55 was too low to be of clinical importance. Copyright © 1996 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]