Plasma Levels of Tumor Necrosis Factor Superfamily Molecules Are Increased in Bipolar Disorder.
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ABSTRACT:
SUBMITTER: Barbosa IG
PROVIDER: S-EPMC5565083 | biostudies-other | 2017 Aug
REPOSITORIES: biostudies-other
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Project description:Purpose:Retinal ganglion cell (RGC) death is a key feature of glaucoma. Elevated levels of tumor necrosis factor alpha (TNF-?), a pro-inflammatory cytokine, can induce RGC apoptosis and play a critical role in glaucomatous neurodegeneration. Based on the possible role of inflammation and oxidative stress in the pathogenesis of primary open-angle glaucoma (POAG), we investigated the association between plasma levels of TNF-? and POAG or its clinical indices in comparison to non-glaucomatous controls. Patients and methods:In a case-control retrospective cohort of 51 POAG cases and 88 controls, plasma TNF-? levels were measured using an enzyme-linked immunosorbent assay (ELISA). The assay was performed in duplicates on an automated ELISA analyzer. Results:Mean TNF-? level was significantly elevated in POAG cases (1.88 ± 2.17 pg/mL) than the controls (0.93 ± 1.49 pg/mL; p = 0.003). The overall dose-response trend was significant (?2 = 6.12, df = 2; p = 0.047). No statistical difference was seen in age, gender and systemic disease distribution. A modest negative and significant correlation was seen between TNF-? level and number of antiglaucoma medications, an important clinical index of POAG severity. Moreover, logistic regression analysis showed that the risk of POAG was most significantly affected by TNF-? level and not by age and sex. Conclusion:High systemic level of an inflammatory cytokine, TNF-?, is associated with POAG; however, its possible use as a biomarker for early glaucoma diagnosis and/or disease severity needs further investigation.
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Project description:Members of the tumor necrosis factor receptor (TNFR) superfamily control cell fate determination, including cell death and differentiation. Fas (CD95) is the prototypical "death receptor" of the TNFR superfamily and signals apoptosis through well established pathways. In the adult nervous system, Fas induces apoptosis in the context of neuropathology such as stroke or amyotrophic lateral sclerosis. However, during nervous system development, Fas promotes neurite growth and branching. The molecular mechanisms underlying Fas-induced process formation and branching have remained unknown to date. Here, we define the molecular pathway linking Fas to process growth and branching in cell lines and in developing neurons. We describe a new cytoplasmic membrane proximal domain (MPD) that is essential for Fas-induced process growth and that is conserved in members of the TNFR superfamily. We show that the Fas MPD recruits ezrin, a molecule that links transmembrane proteins to the cytoskeleton, and activates the small GTPase Rac1. Deletion of the MPD, but not the death domain, abolished Rac1 activation and process growth. Furthermore, an ezrin-derived inhibitory peptide prevented Fas-induced neurite growth in primary neurons. Our results define a new domain, topologically and functionally distinct from the death domain, which regulates neuritogenesis via recruitment of ezrin and activation of Rac1.
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Project description:ObjectiveTumor necrosis factor receptor-associated periodic syndrome (TRAPS) is an autoinflammatory syndrome associated with mutations in the gene that encodes tumor necrosis factor receptor superfamily 1A (TNFRSF1A). The purpose of this study was to describe a novel TNFRSF1A mutation (C43S) in a patient with TRAPS and to examine the effects of this TNFRSF1A mutation on tumor necrosis factor alpha (TNFalpha)-induced signaling in a patient-derived primary dermal fibroblast line.MethodsTNFRSF1A shedding from neutrophils was measured by flow cytometry and enzyme-linked immunosorbent assay (ELISA). Primary dermal fibroblast lines were established from the patient with the C43S TRAPS mutation and from healthy volunteers. Activation of NF-kappaB and activator protein 1 (AP-1) was evaluated by electrophoretic mobility shift assays. Cytokine production was measured by ELISA. Cell viability was measured by alamar blue assay. Apoptosis was measured by caspase 3 assay in the fibroblasts and by annexin V assay in peripheral blood mononuclear cells.ResultsActivation-induced shedding of the TNFRSF1A from neutrophils was not altered by the C43S TRAPS mutation. TNFalpha-induced activation of NF-kappaB and AP-1 was decreased in the primary dermal fibroblasts with the C43S TNFRSF1A mutation. Nevertheless, the C43S TRAPS fibroblasts were capable of producing interleukin-6 (IL-6) and IL-8 in response to TNFalpha. However, TNFalpha-induced cell death and apoptosis were significantly decreased in the samples from the patient with the C43S TRAPS mutation.ConclusionThe C43S TNFRSF1A mutation results in decreased TNFalpha-induced nuclear signaling and apoptosis. Our data suggest a new hypothesis, in that the C43S TRAPS mutation may cause the inflammatory phenotype by increasing resistance to TNFalpha-induced apoptosis.
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Project description:As the use of lenalidomide expands, the poorly understood phenomenon of lenalidomide-induced thyroid abnormalities will increase. In this study, we compared rates of therapy-induced hypothyroidism in 329 patients with diffuse large B-cell lymphoma (DLBCL) treated with conventional chemotherapy (DLBCL-c) or conventional chemotherapy plus lenalidomide (DLBCL-len). We measured serum levels of tumor necrosis factor α, interferon gamma, interleukin 6, interleukin 12, and interleukin 15 before and after treatment. We found a significantly higher rate of therapy-induced hypothyroidism in the DLBCL-len group (25.8% vs. 1.3%), and we found a statistically significant increase in serum tumor necrosis factor α in patients with lenalidomide-induced hypothyroidism.
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Project description:Bipolar disorder (BD) is a mental disorder characterized by extreme changes in mood polarity. It is also characterized by cognitive and metabolic dysfunctions. Fibroblast growth factor 21 (FGF21) is an endocrine protein that has a multifaceted function such as glucose and lipid regulation in the periphery, and neuroprotection and induction of synaptic plasticity in the central nervous system. Previous studies reported inconsistent results concerning peripheral FGF21 levels in patients with BD. In this study, we compared plasma FGF21 levels between 26 patients with BD and 51 healthy controls using a human FGF21 ELISA Kit. There was no significant difference in plasma FGF21 levels between the patients and controls. We found significant positive correlations between plasma FGF21 levels and some cognitive parameters (word association and motor speed). If our results are replicated that higher peripheral FGF21 may be associated with better cognitive performance in patients with BD.
| S-EPMC7722655 | biostudies-literature
Project description:Background:Tumor necrosis factor alpha (TNF-?) is a pro-inflammatory cytokine, which plays a role in glaucomatous neurodegeneration. Based on the plausible role of inflammation in the pathogenesis of pseudoexfoliation glaucoma (PEG), we investigated whether there is any relationship between the levels of plasma TNF-? and PEG or any of its clinical indices in comparison to normal controls. Methods:The study was designed as a retrospective analysis. Plasma samples from 49 PEG patients and 88 non-glaucomatous controls were evaluated for TNF-? levels using an enzyme-linked immunosorbent assay (ELISA). The assay was performed in duplicates on a biochemical/ELISA analyzer. Results:The two study groups were similar in age, sex and systemic disease distribution. The mean TNF-? concentration was significantly higher in the PEG patients (5.54±4.58 pg/mL) than in the control subjects (0.93±1.49 pg/mL; 95% confidence interval [CI] =3.50-5.72; p=0.000). The overall dose-response trend was significant (?2=57.07, df=2; p=0.000). A moderate positive and significant correlation was seen between TNF-? level and cup/disc ratio, an important clinical index for PEG. Besides, binary logistic regression analysis showed that the risk of PEG was most significantly affected by TNF-? level as compared to no association with age and sex. In receiver operating characteristic analysis, the area under the curve was 0.777 (95% CI =0.682-0.872) and statistically significant (p=0.000). Conclusion:Elevated systemic levels of inflammatory marker, TNF-?, are associated with PEG and may possibly serve as a biomarker for undiagnosed early glaucoma and/or as a marker for disease progression.
| S-EPMC5775737 | biostudies-literature
Project description:The tumor necrosis factor (TNF) ligand and cognate TNF receptor superfamilies constitute an important regulatory axis that is pivotal for immune homeostasis and correct execution of immune responses. TNF ligands and receptors are involved in diverse biological processes ranging from the selective induction of cell death in potentially dangerous and superfluous cells to providing costimulatory signals that help mount an effective immune response. This diverse and important regulatory role in immunity has sparked great interest in the development of TNFL/TNFR-targeted cancer immunotherapeutics. In this review, I will discuss the biology of the most prominent proapoptotic and co-stimulatory TNF ligands and review their current status in cancer immunotherapy.
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Project description:PurposeOrexins are hypothalamic neuropeptides involved in the regulation of sleep, appetite and arousal. An altered orexin system has been implicated in the pathophysiology of psychiatric disorders. This study aimed to examine whether plasma orexin-A levels differ in patients with schizophrenia, major depressive disorder (MDD), or bipolar disorder (BD) compared to in healthy controls. We also examined the possible correlations between plasma orexin-A levels and clinical variables.Patients and methodsAll participants were Japanese. The sample consisted of 80 patients with schizophrenia (42 women, 52.5%; mean age 36.8 years), 80 patients with MDD (43 women, 53.8%; 43.7 years), and 40 patients with BD (24 women, 60%; 41.1 years), as well as 80 healthy controls (48 women, 60%; 47.0 years). Plasma orexin-A levels were quantified by an enzyme-linked immunosorbent assay.ResultsMean orexin-A levels were significantly different across the four diagnostic groups (F=4.09; df=3; p=0.007, η2 =0.06). In particular, the patients with BD showed significantly lower orexin-A levels than did the controls. When the median value of the control group (109.8 pg/ml) was set as a cut-off value, subjects whose orexin-A levels were below the cut-off were more common in all psychiatric groups (schizophrenia: 73.8%, x2 =9.56, df=1, p=0.003, OR=2.81, 95% CI: 1.45 to 5.45, d=0.57; MDD: 78.5%, x2 =14.02, df=1, p<0.001, OR=3.65, 95% CI: 1.82 to 7.29, d=0.72; BD: 87.5%, x2 =16.0, df=1, p<0.001, OR=7.00, 95% CI: 2.49 to 19.70, d=1.07). We found no association between plasma orexin-A levels and any clinical symptoms, depression severity, or medication doses.ConclusionOur results suggest that plasma orexin-A levels are reduced in patients with BD.
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Project description:The evolution of the tumor necrosis factor superfamily (TNFSF) in early vertebrates is inferred by comparing the TNFSF genes found in humans and nine fishes: three agnathans, two chondrichthyans, three actinopterygians, and the sarcopterygian Latimeria chalumnae. By combining phylogenetic and synteny analyses, the TNFSF sequences detected are classified into five clusters of genes and 24 orthology groups. A model for their evolution since the origin of vertebrates is proposed. Fifteen TNFSF genes emerged from just three progenitors due to the whole-genome duplications (WGDs) that occurred before the agnathan/gnathostome split. Later, gnathostomes not only kept most of the genes emerged in the WGDs but soon added several tandem duplicates. More recently, complex, lineage-specific patterns of duplications and losses occurred in different gnathostome lineages. In agnathan species only seven to eight TNFSF genes are detected, because this lineage soon lost six of the genes emerged in the ancestral WGDs and additional losses in both hagfishes and lampreys later occurred. The orthologs of many of these lost genes are, in mammals, ligands of death-domain-containing TNFSF receptors, indicating that the extrinsic apoptotic pathway became simplified in the agnathan lineage. From the patterns of emergence of these genes, it is deduced that both the regulation of apoptosis and the control of the NF-κB pathway that depends in modern mammals on TNFSF members emerged before the ancestral vertebrate WGDs.
| S-EPMC7674686 | biostudies-literature
Project description:Basing on the assumption that frontotemporal lobar degeneration (FTLD), schizophrenia and bipolar disorder (BPD) might share common aetiological mechanisms, we analyzed genetic variation in the FTLD risk gene progranulin (GRN) in a German population of patients with schizophrenia (n = 271) or BPD (n = 237) as compared with 574 age-, gender- and ethnicity-matched controls. Furthermore, we measured plasma progranulin levels in 26 German BPD patients as well as in 61 Italian BPD patients and 29 matched controls.A significantly decreased allelic frequency of the minor versus the wild-type allele was observed for rs2879096 (23.2 versus 34.2%, P<0.001, OR:0.63, 95%CI:0.49-0.80), rs4792938 (30.7 versus 39.7%, P = 0.005, OR: 0.70, 95%CI: 0.55-0.89) and rs5848 (30.3 versus 36.8, P = 0.007, OR: 0.71, 95%CI: 0.56-0.91). Mean±SEM progranulin plasma levels were significantly decreased in BPD patients, either Germans or Italians, as compared with controls (89.69±3.97 and 116.14±5.80 ng/ml, respectively, versus 180.81±18.39 ng/ml P<0.001) and were not correlated with age.In conclusion, GRN variability decreases the risk to develop BPD and schizophrenia, and progranulin plasma levels are significantly lower in BPD patients than in controls. Nevertheless, a larger replication analysis would be needed to confirm these preliminary results.
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