Tumor Necrosis Factor Gene Research Articles

Sustained reversal of central neuropathic pain induced by a single intrathecal injection of adenosine A2A receptor agonists

Central neuropathic pain is a debilitating outcome of spinal cord injury (SCI) and current treatments to alleviate this pain condition are ineffective. A growing body of literature suggests that activating adenosine A2A receptors (A2ARs) decreases the production of proinflammatory cytokines and increases the production of anti-inflammatory cytokines. Here, the effect of administering intrathecal A2AR agonists on central neuropathic pain was measured using hindpaw mechanical allodynia in a rat model of SCI termed spinal neuropathic avulsion pain (SNAP). Other models of SCI cause extensive damage to the spinal cord, resulting in paralysis and health problems. SNAP rats with unilateral low thoracic (T13)/high lumbar (L1) dorsal root avulsion develop below-level bilateral allodynia, without concomitant motor or health problems. A single intrathecal injection of the A2AR agonist 2-p-(2-carboxyethyl)phenethylamino-5′-N-ethylcarboxamido adenosine HCl (CGS21680) reversed SCI-induced allodynia for at least 6 weeks. The reversal is likely in part mediated by interleukin (IL)-10, as intrathecally administering neutralizing IL-10 antibodies 1 week after CGS21680 abolished the anti-allodynic effect of CGS21680. Dorsal spinal cord tissue from the ipsilateral site of SCI (T13/L1) was assayed 1 and 6 weeks after CGS21680 for IL-10, CD11b, and tumor necrosis factor (TNF) gene expression. CGS21680 treatment did not change IL-10 gene expression but did significantly decrease CD11b and TNF gene expression at both timepoints. A second A2AR agonist, 4-(3-(6-amino-9-(5-cyclopropylcarbamoyl-3,4-dihydroxytetrahydrofuran-2-yl)-9H-purin-2-yl)prop-2-ynyl)piperidine-1-carboxylic acid methyl ester (ATL313), was also able to significantly prevent and reverse SCI-induced allodynia for several weeks after a single intrathecal injection, providing converging lines of evidence of A2AR involvement. The enduring pain reversal after a single intrathecal injection of A2AR agonists suggests that A2AR agonists could be exciting new candidates for treating SCI-induced central neuropathic pain.

Role of Complex Epigenetic Switching in Tumor Necrosis Factor-α Upregulation in the Prefrontal Cortex of Suicide Subjects.

Proinflammatory cytokines have recently received considerable attention for their role in suicidal behavior; however, how the expression of cytokine genes is regulated is not clearly known. The authors examined underlying mechanisms of critical cytokine gene tumor necrosis factor-alpha (TNF-α) dysregulation in the brains of individuals who died by suicide. TNF-α expression was examined in the dorsolateral prefrontal cortex of the postmortem brains of persons with and without major depressive disorder who died by suicide and of persons with major depressive disorder who died of causes other than suicide. The role of putative microRNAs targeting TNF-α and RNA-binding protein Hu antigen R (HuR) was tested with in vitro and in vivo approaches and by examining expression of transactivation response RNA binding protein (TRBP). Genetic influence on TNF-α expression was determined by expression quantitative trait loci analysis and by genotyping three single-nucleotide polymorphisms in the promoter region of the TNF-α gene. Promoter methylation of TNF-α was determined by using methylated DNA immunoprecipitation assay. Expression of miR-19a-3p and TNF-α was also determined in the peripheral blood mononuclear cells of 12 healthy control subjects and 12 currently depressed patients with severe suicidal ideation. TNF-α expression was significantly higher in the dorsolateral prefrontal cortex of individuals who died by suicide, regardless of psychiatric diagnosis. Its expression level was also increased in individuals with major depressive disorder who died by causes other than suicide. On the other hand, expression of miR-19a-3p was upregulated specifically in individuals who died by suicide. In a preliminary observation, similar upregulation of TNF-α and miR-19a-3p was observed in the peripheral blood mononuclear cells of depressed patients with suicidal ideation. Despite its ability to directly target TNF-α in vitro, miR-19a-3p showed no interaction with TNF-α in the dorsolateral prefrontal cortex. HuR potentially stabilized TNF-α transcript, presumably by sequestering its 3' untranslated region from miR-19a-3p-mediated inhibition. Furthermore, decreased TRBP expression supported abnormality in the interaction between miR-19a-3p and TNF-α. Additionally, TNF-α transcriptional upregulation was associated with promoter hypomethylation, whereas no genetic influence on altered TNF-α or miR-19a-3p expression was observed in individuals who died by suicide. The data in this study provide mechanistic insights into the dysregulation of the TNF-α gene in the brains of individuals who died by suicide, which could potentially be involved in suicidal behavior.

Chia (Salvia hispanica) harvest residue induces cytokine expression in rabbits

The seed of chia plant (Salvia hispanica) is characterized by a high content of polyunsaturated fatty acids, which is an important source of -linolenic acid for human and animal consumption. During the harvest of the seed, waste is generated that contains remnants of leaves, stems and some seeds, which is generally discarded. The objective of the present work was to evaluate the eect of chia seed residue (CSR) on protein expression of the rabbit immune system, when added as a supplement in the diets of animals deliberately induced to an intestinal infection. Twenty rabbits (New Zealand x California) were randomly distributed in five treatments and fed fieve diets with different percentages of CSR inclusion (0, 10, 20, 30 and 40%). Quantification of the relative expression of the anti-inflammatory Interleukin-10 (IL-10) and Tumor Necrosis Factor (TNF-α) genes showed that as CSR inclusion levels increased up to 40%, mRNA expression of IL-10 increased significantly (22.4-fold) with respect to the control, while TNF- mRNA expression was inversely proportional, where a signicant increase (7.47-fold) in mRNA expression was found in the control group. It is concluded that the indirect inclusion of α-linolenic acid through the consumption of CSR induces a positive response in the immune system of the rabbits and represents an alternative for the formulation of rations with nutraceutical effects.

Impact of gene polymorphism of TNF-α rs 1800629 and TNF-β rs 909253 on plasma levels of South Indian breast cancer patients.

Inflammation plays a lead role in the tumor microenvironment and promotes metastasis. Single-nucleotide polymorphism (SNP) in the tumor necrosis factor (TNF) gene locus may alter the expression of genes and proteins. The objective of the study is to find the distribution of genetic polymorphism in the sites of TNF-α -308G>A and TNF- β +252A>G in breast cancer and evaluate polymorphism effects on plasma levels. The study group consisted of 109 invasive ductal primary breast cancer patients and 75 age-matched healthy female controls. Plasma cytokine concentrations were measured by the MILLIPLEX® MAP Human Cytokine/Chemokine Panel magnetic bead kits. The genotyping procedure for SNP included allele-specific polymerase chain reaction for TNFα and restriction fragment length polymorphism for TNFβ. Odds ratio with 95% confidence interval showed that these polymorphisms were not a causative risk factor, and both polymorphisms were consistent with Hardy-Weinberg equilibrium. Plasma TNFα and TNFβ median concentrations were significantly higher in cases when compared to controls (P < 0.01). When plasma TNFα levels were grouped under polymorphic subtypes, patients with mutant TNF- α -308A allele showed significantly higher values (P < 0.001). In addition, plasma TNFα values were significantly elevated in mutant TNF-β +252G allele (P < 0.01). This study demonstrated that there is no significant association between SNPs and breast cancer susceptibility in South Indian population. However, plasma TNFα level is significantly elevated with mutant-recessive TNF-α -308 A and TNF-β +252 G alleles of patients.

The correlation between tumor necrosis factor gene polymorphism and diabetic retinopathy

Aim: Some studies showed that tumor necrosis factor gene polymorphism related to the progression of diabetes mellitus. The aim of this study is to explore the correlation between the gene polymorphism of tumor necrosis factor and diabetic retinopathy in clinical cases. Methods: We took the clinical cases as research subjects. The patients with type I and type II diabetes mellitus who had retinopathy and no retinopathy were 120 cases and 100 cases. At the same time, we analyzed gene polymorphism of tumor necrosis factor for all the patients (rs1800629). Results: A allelic gene of rs1800629 related to type I diabetes mellitus. We did not find significant correlation between rs1800629 and diabetic retinopathy by adjusting age, gender, duration of diabetes mellitus, HbALc, high blood pressure, kidney disease and other variables. Conclusion: This study has preliminarily confirmed that functional single nucleotide polymorphism A in promoter region related to type I diabetes mellitus, which had no significant correlation with diabetic retinopathy.

Association of polymorphisms in TNF and GRN genes with ankylosing spondylitis in a Chinese Han population.

The aim of this study is to investigate the association of the polymorphisms in tumor necrosis factor (TNF) and granulin (GRN) with ankylosing spondylitis (AS) in a Chinese Han population. Five single nucleotide polymorphisms (SNPs) covering TNF and six SNPs covering GRN were investigated in 861 Chinese Han AS patients and 864 healthy controls. For rs1799964, the C allele was linked to reduced risk of AS (p < 0.0001, OR = 0.60, 95% CI = 0.50-0.71). The carriers of the C/C homozygote showed a significantly lower risk of AS compared with the TT homozygote and the C/T heterozygote under the recessive model (p < 0.0001, OR = 0.23, 95% CI = 0.12-0.45). For rs1800629, the A allele was also linked to reduced risk of AS (p < 0.0001, OR = 0.54, 95% CI = 0.39-0.74). For rs1800630, the A allele was also linked to reduced risk of AS (p < 0.0001, OR = 0.59, 95% CI = 0.48-0.72). The carriers of the A/A homozygote showed a significantly lower risk of AS compared with the C/C homozygote and the A/C heterozygote under the recessive model (p < 0.0001, OR = 0.18, 95% CI = 0.07-0.47). For rs769178, the T allele was linked to increased risk of AS (p < 0.0001, OR = 2.59, 95% CI = 2.18-3.09). The carriers of the T/T homozygote showed a significantly higher risk of AS compared with the GG homozygote and the G/T heterozygote under the recessive model (p < 0.0001, OR = 3.34, 95 %CI = 1.95-5.72). There was no significant difference between the AS patients and the controls in the genotype or allele frequencies of rs361525. For GRN, there was no significant difference between the AS patients and the controls in the genotype or allele frequencies of rs25646, rs3760365, rs3785817, rs4792939, rs5848, rs850713 (p > 0.05). This study indicates that polymorphisms in TNF are related to AS, but polymorphisms in GRN are not related to AS susceptibility in a Chinese Han population.

The Neuroinflammatory Response to Nanopatterning Parallel Grooves into the Surface Structure of Intracortical Microelectrodes

AbstractThe smooth surface structure of intracortical microelectrodes implanted within the nanometer‐scale architecture of brain tissue may contribute to the foreign body response. Here, the neuroinflammatory response to nanopatterning surface grooves etched directly on nonfunctional Michigan‐style microelectrodes is explored. Rats implanted with nanopatterned silicon microelectrodes are compared to smooth control implants to observe the effects the grooves have on neuroinflammation. Histology and real‐time PCR at 2 and 4 weeks postimplantation quantify glial cell reactivity and activation, inflammation, oxidative stress, and neuronal survival. Histological observations of glial cells and blood–brain barrier permeability do not show appreciable differences between the nanopatterned and control implants. However, silicon microelectrodes with nanopatterned grooves have more high mobility group box 1 (HMGB1) gene expression at 2 weeks and less nitric oxide synthase (NOS2) gene expression at 4 weeks compared to control surfaces. Control samples have increased NOS2, HMGB1, and tumor necrosis factor gene expression from 2 to 4 weeks, while nanopatterned implants have significant decrease in CD14 gene expression from 2 to 4 weeks. Collectively the results indicate that etching nanopatterned grooves do not reduce histological markers of neuroinflammation compared to control implants, but gene expression results encourage further investigation.

TNF-α blockade suppresses pericystic inflammation following anthelmintic treatment in porcine neurocysticercosis.

BackgroundNeurocysticercosis (NCC) is an infection of the brain with the larval cyst of the tapeworm, Taenia solium. Cysticidal treatment induces parasite killing resulting in a post inflammatory response and seizures, which generally requires corticosteroid treatment to control inflammation. The nature of this response and how to best control it is unclear. We investigated the anti-inflammatory effects of pretreatment with etanercept (ETN), an anti-tumor necrosis factor agent, or dexamethasone (DEX), a high potency corticosteroid, on the post treatment inflammatory response in naturally infected pigs with neurocysticercosis after a single dose of the cysticidal drug praziquantel (PZQ).Methodology/Principal findingsWe followed the methods from a previously developed treatment model of NCC in naturally infected swine. The four study groups of infected pigs included 3 groups treated with PZQ on day 0: PZQ-treated alone (100 mg/kg PO; n = 9), pretreated with dexamethasone (DEX, 0.2 mg/kg IM administered on days -1, +1 and +3; n = 6), and pretreated with etanercept (ETN, 25 mg IM per animal on days -7 and 0; n = 6). The fourth group remained untreated (n = 3). As measured by quantitative RT-PCR, ETN pretreatment depressed transcription of a wide range of proinflammatory, regulatory and matrix protease encoding genes at 120 hr post PZQ treatment in capsules of cysts that demonstrated extravasated Evans Blue (EB) (a measure of blood brain barrier dysfunction) compared to animals not receiving ETN. Transcription was significantly depressed for the proinflammatory genes tumor necrosis factor (TNF)-α, and interferon (IFN)-γ; the inflammation regulating genes cytotoxic T-lymphocyte-associated protein (CTLA)4, interleukin (IL)-13 and transforming growth factor (TGF)-β; the tissue remodeling genes matrix metalloprotease (MMP)1 and 9, tissue inhibitors of metalloproteases (TIMP)1 and 2, and the genes regulating endothelial function vascular endothelial growth factor (VEGF)1, angiopoietin (Ang)1, Ang 2, and platelet endothelial cell adhesion molecule (PECAM)-1. In contrast, transcription was only modestly decreased in the DEX pretreated pigs compared to PZQ alone, and only for TNF-α, IL-6, IFN-γ, TGF-β and Ang1. IL-10 was not affected by either ETN or DEX pretreatments. The degree of inflammation, assessed by semi-quantitative inflammatory scores, was modestly decreased in both ETN and DEX pretreated animals compared to PZQ treated pigs whereas cyst damage scores were moderately decreased only in cysts from DEX pretreated pigs. However, the proportion of cysts with EB extravasation was not significantly changed in ETN and DEX pretreated groups.Conclusions/SignificanceOverall, TNF-α blockade using ETN treatment modulated expression of a large variety of genes that play a role in induction and control of inflammation and structural changes. In contrast the number of inflammatory cells was only moderately decreased suggesting weaker effects on cell migration into the inflammatory capsules surrounding cysts than on release of modulatory molecules. Taken together, these data suggest that TNF-α blockade may provide a viable strategy to manage post-treatment pericystic inflammation that follows antiparasitic therapy for neurocysticercosis.

Tumor necrosis factor-α (TNF-α) −308 G/A and lymphotoxin-α (LT-α) +252 A/G genetic polymorphisms in Egyptian acute lymphoblastic leukemia

Acute lymphoblastic leukemia (ALL) is one of the most hematological malignancies of lymphoid origin. It has been proposed that deregulation of cytokines could be linked with pathogenesis, progression, and survival in many diseases. Genetic polymorphisms in two important cytokines like tumor necrosis factor-α (TNF-α) −308 and lymphotoxin-α (LT-α) +252 can disturb both their transcription and expression and lead to their high plasma levels. A difference in the occurrence of the polymorphisms in TNF-α −308 G/A and LT-α +252 A/G in ALL cases among several populations with different ethnicities was observed. The study investigated the occurrence and the role of polymorphisms of tumor necrosis factor genes including TNF-α −308 G>A and LT-α +252 A>G in the development of ALL in Egypt. A case-control study was done on 126 newly diagnosed ALL patients (96 pediatric and 30 adult patients); 130 healthy subjects composed the control group. Polymorphism variants of TNF-α and LT-α genes were studied by PCR-RFLP on genomic DNA of all studied individuals. TNF-α −308 G/A polymorphism was statistically significant in ALL pediatric patients (P value = 0.008) with no association with ALL adult patients. TNF AA homozygous variant genotype and the A allele both showed significant risks of the development of pediatric ALL. However, there was no association between LT-α +252 A/G polymorphism in both pediatric and adult ALL. The results show that TNF AA homozygous variant genotype and A allele showed a significant risk of development of pediatric ALL.

Clinical, electrophysiological, genetic, and imaging features of six Chinese Han patients with hereditary neuropathy with liability to pressure palsies (HNPP)

Hereditary neuropathy with liability to pressure palsies (HNPP) is an autosomal dominant peripheral neuropathy caused by mutations in the peripheral myelin protein 22 (PMP22) gene. This study summarizes the clinical, electrophysiological, genetic, and imaging features of six unrelated Chinese Han patients with HNPP. Age of onset was within the second decade in five patients, and 46 years of age in one patient. Weakness or numbness in a unilateral lower extremity was the most common symptom in 5 patients, and bilateral sensorineural hearing loss was also detected in one patient. Electrophysiological presentations suggested demyelinating sensory-motor polyneuropathy in the group. Magnetic resonance imaging (MRI) of the cervical and lumbar spine revealed varying degrees of degeneration in five patients, and mild kyphosis of cervical vertebral bodies in 2 teen-aged patients. In addition, cranial MRI of one patient showed scattered demyelination in the frontal lobes. Targeted next-generation-sequencing (NGS) revealed a PMP22 deletion in five patients and a heterozygous c.199G>A mutation in exon 4 of PMP22 in one patient. The I92V variant of lipopolysaccharide-induced tumor necrosis factor (LITAF) gene was found in one patient. There was no relationship between the Ile92Val variant of LITAF and age of onset in this group, albeit the sample size was very small.

Signaling pathways of docosahexenoic acid-induced apoptosis of prostate cancer cells

Objective To explore how docosahexenoic acid (DHA) changes apoptosis signaling pathways to further lead to apoptosis of prostate cancer cells. Methods RT2 Profiler PCR Arrays were used to screen the targets of DHA-induced prostate cancer cells apoptosis (10 apoptosis genes were up-regulated and 5 apoptosis genes were down-regulated). Real-time quantitative polymerase chain reaction (Real-time PCR) was used as reliable tools to validate the results. Results As compared with bovine serum albumin (BSA), after incubation with DHA for 24 h, the transcriptional level of Caspase family: Caspase-1, Caspase-3 and Caspase-9 in DU145 cells were increased 2.06, 4.88 and 12.10 times respectively; The transcriptional level of pro-apoptotic genes B cell lymphoma/leukemia-2 associated X protein (bax) was increased 2.93 times and B cell lymphoma/leukemia-2 (bcl-2)/bax ratio increased. Cell death inducing related genes CIDEA and DFFA were increased 2.34, 3.21 times respectively; Tumor necrosis factor related genes LTA and tumor necrosis factor (TNF) were increased 2.04 and 2.24 times respectively; The expression of tumor protein P53 (TP53) gene mRNA increased 2.97 times. In addition, as compared with the BSA control group, after incubation with DHA for 24 h, the transcriptional levels of apoptosis inducing factor 1 (AIFM1), Akt1, BH3 locus death inducing gene (BID), BIRC6 and X-linked inhibitor of apoptosis protein (XIAP) were decreased. After DHA treatment for 24 h, the mRNA expression of Caspase-1, Caspase-3, Caspase-9 and Caspase-12 was increased respectively. Moreover, the expression of Caspase-3, Caspase-9 and Caspase-12 had a dose-dependent relationship with DHA concentration. The mRNA expression of bax, CIDEA, DFFA, TP53 and TNF normalized with TATA box binding protein (TBP) in 24 h DHA-treated DU145 cells was increased obviously, and the expression of bax, CIDEA and TNF had a dose-dependent relationship with DHA concentration. The mRNA expression of AIFM1, protein kinase B (Akt1), BID, BIRC6 and XIAP was decreased obviously after incubation with different concentrations of DHA for 24 h, and the expression of bax, CIDEA and TNF had a dose-dependent relationship with DHA concentration. Conclusion DHA can change the related genes expression of apoptosis signaling pathways in Caspase family, by this way it can induce the apoptosis of prostate cancer cells. Key words: Prostatic carcinoma; Androgen resistance prostate cancer; Polyunsaturated fatty acids; Docosahexenoic acid

Baicalin Inhibits Inflammatory Responses to Interleukin-1β Stimulation in Human Chondrocytes.

A mix of flavonoids comprising baicalin (BA) and catechin showed effective impacts on controlling the progress of knee osteoarthritis (OA). However, little is known about the underlying mechanisms. The influences of BA on the transcriptional levels of a series of proinflammatory genes were measured using real-time reverse transcription and polymerase chain reaction (RT-PCR). The expressions of proteins involved in nuclear factor-κB (NF-κB) activation were detected by Western blot. The in vitro results were confirmed in a mouse OA model. We found that BA treatment led to remarkable reductions of OA-related proinflammatory gene expressions, including interleukin (IL)-6, tumor necrosis factor (TNF), chemokine (C-X-C motif) ligand 1 (CXCL1), and CXCL10. The transcriptional levels of inducible nitric oxide synthase (iNOS/Nos2), matrix metalloproteinases (MMP)3, and MMP13 were significantly inhibited by BA. We measured the productions of nitrite and prostaglandin E2 from human chondrocytes and BA was shown to reduce their productions. On the contrary, mRNA levels of aggrecan and collagen-II were enhanced by BA treatment. The inhibitory role of BA on OA may possibly be mediated by NF-κB signaling because of comparable decreases of phosphorylated (p)-p65 and p-IκBα and less p65 translocation in the nucleus after BA treatment. In OA mice model, BA significantly reduced synovitis scores and related gene expressions, including IL-6, TNF, CXCL1, CXCL10, MMP3, MMP13, and Nos2. In conclusion, BA suppresses the inflammatory responses of human chondrocytes to IL-1β stimulation, and NF-κB signaling may be involved in the mechanisms of BA functions.

Lipases and lipid droplet-associated protein expression in subcutaneous white adipose tissue of cachectic patients with cancer

BackgroundCancer cachexia is a multifactorial metabolic syndrome characterized by marked loss of adipose tissue and skeletal muscle. Fat loss from adipose tissue in cancer cachexia is partly the result of increased lipolysis. Despite the growing amount of studies focused on elucidating the mechanisms through which lipolysis-related proteins regulate the lipolytic process, there are scarce data concerning that profile in the adipose tissue of cancer cachectic patients. Considering its fundamental importance, it was our main purpose to characterize the expression of the lipolysis-related proteins in the white adipose tissue of cachectic cancer patients.MethodsPatients from the University Hospital were divided into three groups: control, cancer cachexia (CC), and weight-stable cancer patients (WSC). To gain greater insight into adipose tissue wasting during cancer cachexia progression, we have also analyzed an experimental model of cachexia (Walker 256 carcinosarcoma). Animals were divided into: control, intermediate cachexia (IC) and terminal cachexia (TC). Subcutaneous white adipose tissue of patients and epidydimal white adipose tissue of animals were investigated regarding molecular aspects by determining the protein content and gene expression of hormone-sensitive lipase (HSL), adipose triglyceride lipase (ATGL), comparative gene identification-58 (CGI-58), perilipin 1, leptin, adiponectin, visfatin, and tumour necrosis factor alpha (TNF-alpha).ResultsWe found augmented lipolysis in CC associated with increased HSL expression, as well as upregulation of ATGL expression and reduction in perilipin 1 content. In IC, there was an imbalance in the secretion of pro- and anti-inflammatory factors. The alterations at the end-stage of cachexia were even more profound, and there was a reduction in the expression of almost all proteins analyzed in the animals.ConclusionsOur findings show that cachexia induces important morphological, molecular, and humoral alterations in the white adipose tissue, which are specific to the stage of the syndrome.

A C1qDC Protein (HcC1qDC6) with Three Tandem C1q Domains Is Involved in Immune Response of Triangle-Shell Pearl Mussel (Hyriopsis cumingii).

C1q-domain-containing (C1qDC) proteins are a family of proteins with a globular C1q (gC1q) domain and participate in several immune responses. In this study, a C1qDC gene was identified from the triangle-shell pearl mussel Hyriopsis cumingii (designated as HcC1qDC6). This gene has a full-length cDNA of 1782 bp and an open reading frame of 1,335 bp that encodes a 444-amino acid polypeptide containing three gC1q domains. HcC1qDC6 contains at least five exons and four introns. The mRNA transcripts of HcC1qDC6 were found to have the highest expression levels in the mantle tissue. The expression levels in the mantle and hepatopancreas were significantly upregulated by Staphylococcus aureus and Vibrio parahaemolyticus challenges. Moreover, knockdown of HcC1qDC6 inhibits the expression of two immune-related genes (tumor necrosis factor and whey acidic protein). The recombinant proteins of C1q1, C1q2, and C1q3 all exhibit a binding activity against seven bacterial species and directly bind to peptidoglycan and lipopolysaccharide. The results indicate that HcC1qDC6 is involved in the innate immunity of H. cumingii.

Association between single nucleotide polymorphisms of tumor necrosis factor gene and grade II-IV acute GvHD: a systematic review and meta-analysis.

Acute GvHD (aGvHD) complicates up to 50% of allogeneic hematopoietic cell transplants and pre-transplant estimation of its risk can guide prophylaxis, monitoring and early intervention strategies. Inspired by the role of tumor necrosis factor alpha (TNFα) in the pathogenesis of aGvHD and the inconsistency of the association studies exploring single nucleotide polymorphisms (SNPs) of the TNF gene, we conducted a systematic review and meta-analysis of the available reports using PubMed and EMBASE. Original human studies reporting on the association between recipient TNF SNPs and grade II-IV aGvHD in a format convertible to effect size and confidence interval were included. One of the two most widely investigated SNPs (rs361525G>A) was marginally associated with increased risk of grade II-IV aGvHD in random-effects meta-analysis of six studies (627 patients in total, risk ratio=1.29, 95% confidence interval=0.99-1.69, P=0.06). If this result is validated in a large cohort with uniform conditioning and GvHD prophylaxis, TNF rs361525G>A may become a useful tool for aGvHD risk estimation before the transplant.

Maternal exposure to selenium and cadmium, fetal growth, and placental expression of steroidogenic and apoptotic genes

BackgroundCadmium (Cd) and selenium (Se) antagonistically influence redox balance and apoptotic signaling, with Cd potentially promoting and Se inhibiting oxidative stress and apoptosis. Alterations to placental redox and apoptotic functions by maternal exposure to Cd and Se during pregnancy may explain some of the Cd and Se associations with fetal development. ObjectivesInvestigate associations between Cd and Se concentrations in maternal toenails with placental expression patterns of tumor necrosis factor (TNF) and steroidogenic genes involved in redox reactions and test associations with fetal growth. MethodsIn a sub-sample from the Rhode Island Child Health Study (n = 173), we investigated the relationships between: (1) maternal toenail Cd and Se concentrations and fetal growth using logistic regression, (2) Cd and Se interactions with factor scores from placental TNF and steroidogenic expression patterns (RNAseq) using linear models, and (3) TNF and steroidogenic expression factors with fetal growth via analysis of covariance. ResultsSe was associated with decreased odds of intrauterine growth restriction (IUGR) (OR = 0.27, p-value = 0.045). Cd was associated with increased odds of IUGR (OR = 1.95, p-value = 0.13) and small for gestational age (SGA) births (OR = 1.46, p-value = 0.11), though not statistically significant. Cd and Se concentrations were antagonistically associated with placental TNF and steroidogenic expression patterns, which also differed by birth size. ConclusionsSe may act as an antagonist to Cd and as a modifiable protective factor in fetal growth restriction, and these data suggest these effects may be due to associated variations in the regulation of genes involved in placental redox balance and/or apoptotic signaling.

Correspondence on Lovell et al.: identification of chicken genes previously assumed to be evolutionarily lost

Through RNA-Seq analyses, we identified 137 genes that are missing in chicken, including the long-sought-after nephrin and tumor necrosis factor genes. These genes tended to cluster in GC-rich regions that have poor coverage in genome sequence databases. Hence, the occurrence of syntenic groups of vertebrate genes that have not been observed in Aves does not prove the evolutionary loss of such genes.Please see related Research article: http://dx.doi.org/10.1186/s13059-014-0565-1 and Please see response from Lovell et al: https://www.dx.doi.org/10.1186/s13059-017-1234-y

Vitamin D inhibits the Staphylococcal enterotoxin B-induced expression of tumor necrosis factor in microglial cells.

Microglial cells play a crucial role in inflammatory responses in neural tissue. Vitamin D (VitD3) deficiency is associated with the pathogenesis of inflammation. Staphylococcal enterotoxin B (SEB) is a superantigen and can initiate inflammation. This study tests a hypothesis that VitD3 deficiency upregulates the expression of tumor necrosis factor (TNF) in microglial cells. Microglial cells were isolated from the mouse brain. The microglial cells were cultured in the presence or absence of VitD3 or/and SEB. The expression of TNF in the microglial cells was assessed by RT-qPCR and Western blotting. We observed that SEB increased the expression of TNF in microglial cells. The presence of calcitriol (an active form of VitD3) inhibited the SEB-induced TNF production by microglial cells in a dose-dependent manner. Exposure to SEB increased the binding of vitamin D receptor (VDR) to the TNF promoter, which was inhibited by the presence of calcitriol with the mechanism being the formation of a complex of VDR and LITAF (a transcription factor of TNF) in microglial cells; the complex prevented the binding of LITAF to the promoter of the TNF gene. Exposure to calcitriol also increased the expression of IL-10 in microglial cells; the inhibition of SEB-induced TNF expression was partially due to the IL-10 induced by calcitriol (Heine G, Niesner U, Chang HD, teinmeyer A, Zügel U, Zuberbier T, et al. 1,25-dihydroxyvitamin D(3) promotes IL-10 production in human B cells. Eur J Immunol. 2008;38(8):2210-8). Hormonal vitamin D [calcitriol] can inhibit the SEB-induced TNF expression in microglial cells.

SP and IL-33 together markedly enhance TNF synthesis and secretion from human mast cells mediated by the interaction of their receptors

The peptide substance P (SP) and the cytokine tumor necrosis factor (TNF) have been implicated in inflammatory processes. Mast cells are recognized as important in inflammatory responses. Here, we report that IL-33 (30 ng/mL), a member of the IL-1 family of cytokines, administered in combination with SP (1 µM), markedly increase (by 1,000-fold) TNF gene expression in cultured human LAD2 and primary mast cells derived from umbilical cord blood. SP (0.01-1 μM) and IL-33 (1-100 ng/mL) in combination also greatly stimulate TNF secretion (by 4,500-fold). Pretreatment of LAD2 cells with two different neurokinin-1 (NK-1) receptor antagonists and siRNA inhibits TNF secretion by 50% (P < 0.001) when stimulated by SP and IL-33. Pretreatment of LAD2 cells with a neutralizing antibody for IL-33 receptor, ST2, inhibits TNF secretion by 50% (P < 0.001), and ST2 siRNA decreases TNF secretion by 30% (P < 0.05), when stimulated by SP and IL-33. Surprisingly, NK-1 antagonists also inhibit 50% of TNF secretion (P < 0.001) when stimulated only by IL-33, and ST2 receptor reduction also decreases SP-stimulated TNF secretion by 30% (P < 0.05), suggesting an interaction between NK-1 and ST2 receptors. Moreover, IL-33 increases NK-1 gene and surface protein expression, as well as IKβ-α phosphorylation. Pretreatment of LAD2 cells with 5,7,3',4'-tetramethoxyflavone (methoxyluteolin) (1-100 μM) inhibits (P < 0.001) TNF gene expression (98%) and secretion (64%) at 50 µM and phosphorylation of p-IKB-α at 1 μM when stimulated by SP and IL-33. These findings identify a unique amplification process of TNF synthesis and secretion via the interaction of NK-1 and ST2 receptors inhibitable by methoxyluteolin.

Epigenetic silencing of triple negative breast cancer hallmarks by Withaferin A

Triple negative breast cancer (TNBC) is characterized by poor prognosis and a DNA hypomethylation profile. Withaferin A (WA) is a plant derived steroidal lactone which holds promise as a therapeutic agent for treatment of breast cancer (BC). We determined genome-wide DNA methylation changes in weakly-metastatic and aggressive, metastatic BC cell lines, following 72h treatment to a sub-cytotoxic concentration of WA. In contrast to the DNA demethylating agent 5-aza-2’-deoxycytidine (DAC), WA treatment of MDA-MB-231 cells rather tackles an epigenetic cancer network through gene-specific DNA hypermethylation of tumor promoting genes including ADAM metallopeptidase domain 8 (ADAM8), urokinase-type plasminogen activator (PLAU), tumor necrosis factor (ligand) superfamily, member 12 (TNFSF12), and genes related to detoxification (glutathione S-transferase mu 1, GSTM1), or mitochondrial metabolism (malic enzyme 3, ME3). Gene expression and pathway enrichment analysis further reveals epigenetic suppression of multiple cancer hallmarks associated with cell cycle regulation, cell death, cancer cell metabolism, cell motility and metastasis. Remarkably, DNA hypermethylation of corresponding CpG sites in PLAU, ADAM8, TNSF12, GSTM1 and ME3 genes correlates with receptor tyrosine-protein kinase erbB-2 amplification (HER2)/estrogen receptor (ESR)/progesterone receptor (PR) status in primary BC tumors. Moreover, upon comparing differentially methylated WA responsive target genes with DNA methylation changes in different clinical subtypes of breast cancer patients in the cancer genome atlas (TCGA), we found that WA silences HER2/PR/ESR-dependent gene expression programs to suppress aggressive TNBC characteristics in favor of luminal BC hallmarks, with an improved therapeutic sensitivity. In this respect, WA may represent a novel and attractive phyto-pharmaceutical for TNBC treatment.