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Background: In current literature there are only scarce data on the host inflammatory response during Burkholderia cepacia complex (Bcc) persistence. The primary objective of the present research was to carry out cross-sectional analyses of biomarkers and evaluate disease progression in cystic fibrosis (CF) patients with chronic Bcc infection and pathogen-free ones. The secondary aim was to assess prospectively overall survival of the study participants during up to 8 years of follow-up. Methods: The study included 116 paediatric patients with CF; 47 CF patients were chronically infected with Bcc, and 69 individuals were Bcc free. Plasma and sputum biomarkers (neutrophil elastase, MMP-8, MMP-9, MMP-12, IL-2, IL-4, IL-6, IL-8, IL-10, IL-18, IL-22, IL-23, IL-17, IFN-γ, TGFβ1, TNF-α) were analysed using commercially available kits. Besides, inhibitory effect of dexamethasone on proliferative response of PHA-stimulated peripheral blood lymphocytes had been assessed. Results: Bcc infected patients did not differ from Bcc free ones in demographic and clinical parameters, but demonstrated an increased rate of glucose metabolism disturbances and survival disadvantage during prolong follow-up period. Biomarkers analyses revealed elevated TNF-α and reduced IL-17F levels in sputum samples of Bcc infected patients. These patients also demonstrated improvement of peripheral blood lymphocyte sensitivity to steroid treatment and reduction in plasma pro-inflammatory (IL-17F and IL-18) and anti-inflammatory (TGFβ1 and IL-10) cytokine concentrations. Conclusions: Reduction in IL-17F levels may have several important consequences including increase in steroid sensitivity and glycemic control disturbances. Further investigations are needed to clarify the role of IL-17 cytokines in CF complication development. Low plasma TGFb1 and IL-10 levels in Bcc infected group may be a sign of subverted activity of regulatory T cells. Such immune alterations may be one of the factors contributing to the development of the cepacia syndrome. [ABSTRACT FROM AUTHOR]

Background: Variation in host immune responses to SARS-CoV-2 is regulated by multiple genes involved in innate viral response and cytokine storm emergence like IL-10 and TNFa gene polymorphisms. We hypothesize that IL-10; -592 C > A and − 1082 A > G and TNFa-308 G > A are associated with the risk of SARS-COV2 infections and clinical outcome. Methods: Genotyping, laboratory and radiological investigations were done to 110 COVID-19 patients and 110 healthy subjects, in Ismailia, Egypt. Results: A significant association between the − 592 A allele, A containing genotypes under all models (p < 0.0001), and TNFa A allele with risk to infection was observed but not with the G allele of the − 1082. The − 592 /-1082 CG and the − 592 /-1082/ -308 CGG haplotypes showed higher odds in COVID-19 patients. Severe lung affection was negatively associated with − 592, while positive association was observed with − 1082. Higher D-dimer levels were strongly associated with the − 1082 GG genotype. Survival outcomes were strongly associated with the GA genotype of TNFa. -308 as well as AGG and AAA haplotypes. Conclusion: IL-10 and TNFa polymorphisms should be considered for clinical and epidemiological evaluation of COVID-19 patients. [ABSTRACT FROM AUTHOR]

Background: Variation in host immune responses to SARS-CoV-2 is regulated by multiple genes involved in innate viral response and cytokine storm emergence like IL-10 and TNFa gene polymorphisms. We hypothesize that IL-10; -592 C > A and − 1082 A > G and TNFa-308 G > A are associated with the risk of SARS-COV2 infections and clinical outcome. Methods: Genotyping, laboratory and radiological investigations were done to 110 COVID-19 patients and 110 healthy subjects, in Ismailia, Egypt. Results: A significant association between the − 592 A allele, A containing genotypes under all models (p < 0.0001), and TNFa A allele with risk to infection was observed but not with the G allele of the − 1082. The − 592 /-1082 CG and the − 592 /-1082/ -308 CGG haplotypes showed higher odds in COVID-19 patients. Severe lung affection was negatively associated with − 592, while positive association was observed with − 1082. Higher D-dimer levels were strongly associated with the − 1082 GG genotype. Survival outcomes were strongly associated with the GA genotype of TNFa. -308 as well as AGG and AAA haplotypes. Conclusion: IL-10 and TNFa polymorphisms should be considered for clinical and epidemiological evaluation of COVID-19 patients. [ABSTRACT FROM AUTHOR]

Copyright of Boletín Médico del Hospital Infantil de México is the property of Publicidad Permanyer SLU and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Ischemia/reperfusion injury (IRI) is a common cause of kidney damage, characterized by oxidative stress and inflammation. In this study, we investigated the potential protective effects of IAXO-102, a chemical compound, on experimentally induced IRI in male rats. The bilateral renal IRI model was used, with 24 adult male rats randomly divided into four groups (N=6): sham group (laparotomy without IRI induction), control group (laparotomy plus bilateral IRI for 30 minutes followed by 2 hours of reperfusion), vehicle group (same as control but pre-injected with the vehicle), and treatment group (similar to control but pre-injected with IAXO-102). We measured several biomarkers involved in IRI pathophysiology using enzyme-linked immunosorbent assay (ELISA), including High mobility group box1 (HMGB1), nuclear factor kappa b-p65 (NF-κB p65), interleukin beta-1 (IL-1ß), interleukin-6 (IL-6), tumor necrosis factor-a (TNF-a), 8-isoprostane, Bcl-2 associated X protein (BAX), heat shock protein 27 (HSP27), and Bcl-2. Statistical analysis was performed using one-way ANOVA and Tukey post hoc tests. Our results showed that IAXO-102 significantly improved kidney function, reduced histological alterations, and decreased the inflammatory response (IL-1, IL-6, and TNF) caused by IRI. IAXO-102 also decreased apoptosis by reducing pro-apoptotic Bax and increasing anti-apoptotic Bcl-2 without impacting HSP27. In conclusion, our findings suggest that IAXO-102 had a significant protective effect against IRI damage in the kidneys. [ABSTRACT FROM AUTHOR]

Coronavirus disease 2019 (COVID-19) is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This virus does not only lead to pulmonary infection but can also infect other organs such as the gut, the kidney, or the liver. Recent studies confirmed that severe cases of COVID-19 are often associated with liver damage and liver failure, as well as the systemic upregulation of pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNFa). However, the impact these immune mediators in the liver have on patient survival during SARS-CoV-2 infection is currently unknown. Here, by performing a post-mortem analysis of 45 patients that died from a SARS-CoV-2 infection, we find that an increased expression of TNFA in the liver is associated with elevated mortality. Using publicly available single-cell sequencing datasets, we determined that Kupffer cells and monocytes are the main sources of this TNFa production. Further analysis revealed that TNFa signaling led to the upregulation of pro-inflammatory genes that are associated with an unfavorable outcome. Moreover, high levels of TNFA in the liver were associated with lower levels of interferon alpha and interferon beta. Thus, TNFa signaling in the infected SARS-CoV-2 liver correlates with reduced interferon levels and overall survival time. [ABSTRACT FROM AUTHOR]

Introduction: Post-Traumatic Stress Disorder (PTSD) is a psychological disorder that occurs after a traumatic event in a subset of exposed individuals. This implies the existence of susceptibility factors that foster the development of PTSD. Susceptibility factors are present before trauma and can contribute to the development and maintenance of PTSD after trauma. Manipulation of susceptibility factors may decrease the probability of developing PTSD. A putative susceptibility factor is inflammation. Patients with PTSD have been documented to have a higher pro-inflammatory profile compared to non-PTSD subjects. In addition, they are more likely to develop and die from cardiovascular disease which has a strong inflammation component. It is not known, however, whether inflammation plays a role in developing PTSD or whether reducing inflammation can prevent PTSD. Methods: We used the Revealing Individual Susceptibility to a PTSD-like phenotype (RISP) model to behaviorally classify male rats as resilient or susceptible before trauma and tested their serum and prefrontal cortical (mPFC) levels of IL-1β, IL-6, TNFα, IL-10, IFN IFNγ, and KC/GRO to determine whether inflammation represents a putative susceptibility factor for PTSD. Results: We found elevated IL-6 levels in the mPFC, but not serum, of susceptible rats compared to resilient animals before trauma. Serum and mPFC levels were not correlated in any of the cytokines/chemokines. Rats with high anxiety-like behavior had elevated IL-6 and IL-10 mPFC levels. Acoustic startle responses were not associated with cytokine/chemokine levels. Discussion: Neuroinflammation, rather than systemic inflammation exists in susceptible male rats before trauma and is thus a putative susceptibility factor for PTSD. Thus, susceptibility appears neurogenic in its pathogenesis. The lack of differences between susceptible and resilient rats in serum cytokine/chemokine levels infers that peripheral markers will not be useful in determining susceptibility. Chronic neuroinflammation appears more broadly associated with anxiety rather than startle responses. [ABSTRACT FROM AUTHOR]

Background: Sarcoidosis is a chronic, multisystem inflammatory disorder characterized by non-caseating epithelioid granulomas; infiltration of mononuclear cells; and destruction of microarchitecture in the skin, eye, heart, and central nervous system, and the lung in >90% of cases. XTMAB-16 is a chimeric anti-tumor necrosis factor alpha (TNFa) antibody, distinct from other anti-TNF antibodies based on its molecular structure. The efficacy of XTMAB-16 has not been clinically demonstrated, and it is still undergoing clinical development as a potential treatment for sarcoidosis. The current study demonstrates the activity of XTMAB-16 in a well-established in vitro sarcoidosis granuloma model, although XTMAB-16 is not yet approved by the United States Food and Drug Administration (FDA) for treatment of sarcoidosis, or any other disease. Objective: To provide data to guide safe and efficacious dose selection for the ongoing clinical development of XTMAB-16 as a potential treatment for sarcoidosis. Methods: First, XTMAB-16 activity was evaluated in an established in vitro model of granuloma formation using peripheral blood mononuclear cells from patients with active pulmonary sarcoidosis to determine a potentially efficacious dose range. Second, data obtained from the first-in-human study of XTMAB-16 (NCT04971395) were used to develop a population pharmacokinetic (PPK) model to characterize the pharmacokinetics (PK) of XTMAB-16. Model simulations were performed to evaluate the sources of PK variability and to predict interstitial lung exposure based on concentrations in the in vitro granuloma model. Results: XTMAB-16 dose levels of 2 and 4 mg/kg, once every 2 weeks (Q2W) or once every 4 weeks (Q4W) for up to 12 weeks, were supported by data from the non-clinical, in vitro secondary pharmacology; the Phase 1 clinical study; and the PPK model developed to guide dose level and frequency assumptions. XTMAB-16 inhibited granuloma formation and suppressed interleukin-1ß (IL-1ß) secretion in the in vitro granuloma model with a half maximal inhibitory concentration (IC50) of 5.2 and 3.5 µg/mL, respectively. Interstitial lung concentrations on average, following 2 or 4 mg/kg administered Q2W or Q4W, are anticipated to exceed the in vitro IC50 concentrations. Conclusion: The data presented in this report provide a rationale for dose selection and support the continued clinical development of XTMAB-16 for patients with pulmonary sarcoidosis. [ABSTRACT FROM AUTHOR]

Inflammation is a central pathogenic feature of the acute respiratory distress syndrome (ARDS) in COVID-19. Previous pathologies such as diabetes, autoimmune or cardiovascular diseases become risk factors for the severe hyperinflammatory syndrome. A common feature among these risk factors is the subclinical presence of cellular stress, a finding that has gained attention after the discovery that BiP (GRP78), a master regulator of stress, participates in the SARSCoV-2 recognition. Here, we show that BiP serum levels are higher in COVID-19 patients who present certain risk factors. Moreover, early during the infection, BiP levels predict severe pneumonia, supporting the use of BiP as a prognosis biomarker. Using a mouse model of pulmonary inflammation, we observed increased levels of cell surface BiP (cs-BiP) in leukocytes during inflammation. This corresponds with a higher number of neutrophiles, which show naturally high levels of cs-BiP, whereas alveolar macrophages show a higher than usual exposure of BiP in their cell surface. The modulation of cellular stress with the use of a clinically approved drug, 4-PBA, resulted in the amelioration of the lung hyperinflammatory response, supporting the anti-stress therapy as a valid therapeutic strategy for patients developing ARDS. Finally, we identified stress-modulated proteins that shed light into the mechanism underlying the cellular stress-inflammation network in lungs. [ABSTRACT FROM AUTHOR]

The treatment for tuberculosis (TB), especiallymultidrug-resistant TB (MDRTB), has a prolonged cycle which can last up to a year. This is partially due to the lack of effective therapies. The development of novel anti-TB drugs from the perspective of host immune regulation can provide an important supplement for conventional treatment strategies. Salidroside (SAL), a bioactive component from the Tibetan medicine Rhodiola rosea, has been used in the treatment of TB, although its mechanism remains unclear. Here, the bacteriostatic effect of SAL in vivo was first demonstrated using a zebrafish-M. marinum infection model. To further investigate the underlying mechanism, we then examined the impact of SAL on immune cell recruitment during wound and infection. Increased macrophage and neutrophil infiltrations were found both in the vicinity of the wound and infection sites after SAL treatment compared with control, which might be due to the elevated chemokine expression levels after SAL treatment. SAL treatment alone was also demonstrated to improve the survival of infected zebrafish larvae, an effect that was amplified when combining SAL treatment with isoniazid or rifampicin. Interestingly, the reduced bacterial burden and improved survival rate under SAL treatment were compromised in tnfa-deficient embryos which suggests a requirement of Tnfa signaling on the anti-mycobacterial effects of SAL. In summary, this study provides not only the cellular and molecular mechanisms for the host anti-mycobacterial effects of the Tibetan medicine SAL but also proof of concept that combined application of SAL with traditional first-line anti-TB drugs could be a novel strategy to improve treatment efficacy. [ABSTRACT FROM AUTHOR]

Background. Obesity is associated with dyslipidemia, and excess body fat is associated with unfavorable levels of adipokines and markers of inflammation. The goal of research. To study the level of adipokines and markers of inflammation, their associations with unstable atherosclerotic plaques in men with coronary atherosclerosis on the background of abdominal obesity. Materials and methods. The study involved 82 men aged 40–77 years with coronary atherosclerosis after endarterectomy from the coronary arteries. We divided all men into two groups: 37 men (45.1%) with unstable atherosclerotic plaques, and 45 men (54.9%) who had stable plaques. Obesity was established at a BMI of ≥30 kg/m2. The levels of adipokines and markers of inflammation in the blood were determined by multiplex analysis. Results. In patients with obesity and unstable plaques, the levels of C-peptide, TNFa and IL-6 were 1.8, 1.6, and 2.8 times higher, respectively, than in patients with obesity and stable plaques. The chance of having an unstable plaque increases with an increase in TNFa by 49% in obese patients and decreases with an increase in insulin by 3% in non-obese patients. Conclusions. In men with coronary atherosclerosis and obesity, unstable atherosclerotic plaques in the coronary arteries are directly associated with the level of TNF-α. [ABSTRACT FROM AUTHOR]

Tumor necrosis factor (TNF)-α is a proinflammatory cytokine that plays an important role in the pathogenesis of autoimmune diseases. The aim of the study was to establish an association between TNF-α promoter variability and systemic sclerosis (SSc). The study included 43 SSc patients and 74 controls. Four single nucleotide polymorphisms (rs361525, rs1800629, rs1799724, and rs1799964) located at the promoter of the TNFA gene were genotyped using commercially available TaqMan allelic discrimination assays with real-time PCR. The rs1799724 allele was associated with an increased SSc susceptibility (p = 0.028). In turn, none of the polymorphisms studied were related to the clinical and laboratory parameters of SSc patients, except for a higher prevalence of anti-Ro52 antibodies in the AG rs1800629 genotype in comparison to GG carriers (p = 0.04). Three of four cancer patients had both CT rs1799964 and AG rs361525 genotypes; thus, both of them were related to the increased risk of cancer, as compared to the TT (p = 0.03) and GG carriers (p = 0.0003), respectively. The TNFA C rs1799724 variant is associated with an increased risk of SSc, while the CT rs1799964 and AG rs361525 genotypes might enhance cancer susceptibility in SSc patients, although large observational and experimental studies are needed to verify the above hypothesis. [ABSTRACT FROM AUTHOR]

In recent decades, Rheumatoid arthritis (RA) treatment landscape has evolved with the induction of new biological and targeted therapies that provide significant therapeutic benefits in patients with sustained disease. Tumor necrosis factor inhibitors (TNFi) were the first biologics used in the treatment of RA. Although they present a significant efficacy, an insufficient response of some patients led to further research and discovery of targeted therapies, such as Janus kinase inhibitors (JAKi), which act at a molecular level, regulating many cytokines. Clinical benefits have been seen with both TNFi and JAKi as monotherapy and combined with conventional synthetic disease-modifying antirheumatic drugs. Still, some significant side effects have been reported with JAKi, and several questions remain about their safety and selectivity in action. This review summarizes the current knowledge on the mechanism of action, the clinical efficacy, and safety of TNFi vs. JAKi. TNFi and JAKi are particularly useful in treating inflammatory arthropathies. Both drug categories are recommended by ACR and EULAR institutions in RA patients suffering from moderate to severe disease. Safety data in long-term studies are required to determine the optimal benefit to the risk profile of JAKi use. [ABSTRACT FROM AUTHOR]

Immune checkpoint inhibitors (ICI) have provided significant improvement in clinical outcomes for some patients with solid tumors. However, for patients with head and neck cancer, the response rate to ICI monotherapy remains low, leading to the exploration of combinatorial treatment strategies. In this preclinical study, we use an oncolytic adenovirus (Ad5/3) encoding hTNFα and hIL-2 and non-replicate adenoviruses (Ad5) encoding mTNFα and mIL-2 with ICI to achieve superior tumor growth control and improved survival outcomes. The in vitro effect of Ad5/3-E2F-D24-hTNFa-IRES-hIL-2 was characterized through analyses of virus replication, transgene expression and lytic activity using head and neck cancer patient derived cell lines. Mouse models of ICI naïve and refractory oral cavity squamous cell carcinoma were established to evaluate the local and systemic anti-tumor immune response upon ICI treatment with or without the non-replicative adenovirus encoding mTNFα and mIL-2. We delineated the mechanism of action by measuring the metabolic activity and effector function of CD3+ tumor infiltrating lymphocytes (TIL) and transcriptomic profile of the CD45+ tumor immune compartment. Ad5/3-E2F-D24-hTNFa-IRES-hIL-2 demonstrated robust replicative capability in vitro across all head and neck cell lines screened through potent lytic activity, E1a and transgene expression. In vivo , in both ICI naïve and refractory models, we observed improvement to tumor growth control and long-term survival when combining anti-PD-1 or anti-PD-L1 with the non-replicative adenovirus encoding mTNFα and mIL-2 compared to monotherapies. This observation was verified by striking CD3+ TIL derived mGranzyme b and interferon gamma production complemented by increased T cell bioenergetics. Notably, interrogation of the tumor immune transcriptome revealed the upregulation of a gene signature distinctive of tertiary lymphoid structure formation upon treatment of murine anti-PD-L1 refractory tumors with non-replicative adenovirus encoding mTNFα and mIL-2. In addition, we detected an increase in anti-tumor antibody production and expansion of the memory T cell compartment in the secondary lymphoid organs. In summary, a non-replicative adenovirus encoding mTNFα and mIL-2 potentiates ICI therapy, demonstrated by improved tumor growth control and survival in head and neck tumor-bearing mice. Moreover, the data reveals a potential approach for inducing tertiary lymphoid structure formation. Altogether our results support the clinical potential of combining this adenovirotherapy with anti-PD-1 or anti-PD-L1. [ABSTRACT FROM AUTHOR]

The transcription factor NF-κB plays an important role in modulation of inflammatory pathways, which are associated with inflammatory diseases, neurodegeneration, apoptosis, immune responses, and cancer. Increasing evidence indicates that TRIM proteins are crucial role in the regulation of NF-κB signaling pathways. In this study, we identified TRIM67 as a negative regulator of TNFα-triggered NF-κB activation. Ectopic expression of TRIM67 significantly represses TNFα-induced NF-κB activation and the expression of pro-inflammatory cytokines TNFα and IL-6. In contrast, Trim67 depletion promotes TNFα-induced expression of TNFα, IL-6, and Mcp-1 in primary mouse embryonic fibroblasts. Mechanistically, we found that TRIM67 competitively binding β-transducin repeat-containing protein (β-TrCP) to IκBα results inhibition of β-TrCP-mediated degradation of IκBα, which finally caused inhibition of TNFα-triggered NF-κB activation. In summary, our findings revealed that TRIM67 function as a novel negative regulator of NF-κB signaling pathway, implying TRIM67 might exert an important role in regulation of inflammation disease and pathogen infection caused inflammation. [ABSTRACT FROM AUTHOR]

Intratumoral immunotherapies are entering clinical use but concerns remain regarding their effects on non-injected tumors. Here, we studied the impact of local treatment with an adenovirus coding for TNFa and IL-2 on systemic antitumor response in animals receiving aPD-1 (anti-programmed cell death protein 1) therapy. Using bilateral murine melanoma models, we tested systemic tumor response to combined therapy with anti-PD-1 and an adenovirus coding for TNFa and IL-2 ("virus"). Virus was given intratumorally (to one of the two tumors only) and aPD-1 monoclonal antibody systemically. We evaluated both tumors' response to treatment, overall survival, metastasis development, and immunological mechanisms involved with response. Consistent tumor control was observed in both injected and noninjected tumors, including complete response in all treated animals receiving aPD-1+ virus therapy. Mechanistically, virus injections enabled potent effector lymphocyte response locally, with systemic effects in non-injected tumors facilitated by aPD-1 treatment. Moreover, adenovirus therapy demonstrated immunological memory formation. Virus therapy was effective in preventing metastasis development. Local treatment with TNFa and IL-2 coding adenovirus enhanced systemic response to aPD-1 therapy, by re-shaping the microenvironment of both injected and non-injected tumors. Therefore, our pre-clinical data support the rationale for a trial utilizing a combination of aPD-1 plus virus for the treatment of human cancer. [ABSTRACT FROM AUTHOR]

Copyright of Cumhuriyet Medical Journal is the property of Cumhuriyet Medical Journal and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Background: Gentamicin (GM) is a low-cost, low-resistance antibiotic commonly used to treat gram-negative bacterial diseases. Cisplatin (Csp) is a platinum-derived anti-neoplastic agent. This experiment aimed to identify the early signs of gentamicin and cisplatin-induced nephrotoxicity in rats. Thirty Wistar rats were divided into three groups of 10: a control group, which received no treatment; a gentamicin group administered by a dose of (100 mg/kg, IP) for 7 consecutive days, and a cisplatin group was administered intraperitoneal in a dose of (1.5 mg/kg body weight) repeated twice a week for 3 weeks. Results: Both experimental groups exhibited increased levels of creatinine, urea, and uric acid, with the cisplatintreated group showing higher levels than the gentamicin group. Experimental groups also exhibited significantly increased Malondialdehyde (MDA), reduced glutathione (GSH), and glutathione peroxidase (GSH-Px) with more pronounced effects in the cisplatin-treated group. Further, both experimental groups exhibited significant up-regulation of Tumor Necrosis Factor a (TNF-a), caspase-3, and Bax and down regulation of Bcl-2. Conclusion: These findings confirm the use of necrotic, apoptotic genes as early biomarkers in the detection of tubular kidney damage. Further, cisplatin was shown to have a greater nephrotoxic effect than gentamicin; therefore, its use should be constrained accordingly when co-administered with gentamicin. [ABSTRACT FROM AUTHOR]

Oral carcinogenesis represents a multi-stage process which encompasses several genetic and molecular changes that promote the progression of oral potentially malignant disorders (OPMDs) to oral squamous cell carcinomas (OSCCs). A better understanding of critical pathways governing the progression of OMPDs to OSCCs is critical to improve oncologic outcomes in the future. Previous studies have identified an important role of tumor necrosis factor α (TNFα) and TNF receptor 1 (TNFR1) in the invasiveness of oral cancer cell lines. Here, we investigate the expression of TNFα and TNFR1 in human OPMDs that progress to OSCC compared to non-progressing OPMDs utilizing fluorescent immunohistochemistry (FIHC) to show increased TNFα/TNFR1 expression in progressing OPMDs. In order to interrogate the TNFα/TNFR1 signaling pathway, we utilized a 4-nitroquinoline 1-oxide (4-NQO) mouse model of oral carcinogenesis to demonstrate that TNFα/TNFR1 expression is upregulated in 4-NQO-induced OSCCs. TNFα neutralization decreased serum cytokines, inhibited the development of invasive lesions and reduced tumor-associated neutrophils in vivo. Combined, this data supports the role of TNFα in oral malignant transformation, suggesting that critical immunoregulatory events occur downstream of TNFR1 leading to malignant transformation. Our results advance the understanding of the mechanisms governing OSCC invasion and may serve as a basis for alternative diagnostic and therapeutic approaches to OPMDs and OSCC management. [ABSTRACT FROM AUTHOR]

Activation of transposable elements (TEs) can cause cellular damage. Cytoplasmic nucleic acid sensing pathways evolved to detect pathogens, but can also serve to cull cells with inappropriate TE activation as TEs can be viral mimetics. Epigenetic silencing of TEs is mediated in part by DNA methylation, but it is not clear if TE activation or the immune system contribute to the cellular damage caused by loss of DNA methylation. Here, we provide mechanistic insight into the observation of an activated interferon response in the liver of zebrafish larvae with deletion in critical components of the DNA methylation machinery, uhrf1 and dnmt1. We focus on dissecting the relationship between DNA methylation, TE activation and induction of an immune response through cytoplasmic DNA and double stranded RNA sensing pathways and identify tnfa as a mediator of cell death in the liver of these mutants. Integrated RNAseq and methylome analysis identified LTR transposons as the most upregulated in these mutants and also the most methylated in control larvae, indicating a direct role of DNA methylation in suppressing this TE subclass. RNAseq analysis from these same samples revealed expression signatures of a type-I interferon response and of tnfa activation, mimicking the pattern of gene expression in virally infected cells. CRISPR/Cas9 mediated depletion of the cellular antiviral sensors sting and mavs reduced expression of interferon response genes and tnfa depletion dramatically reduced cell death in uhrf1 mutant livers. This suggests that the antiviral response induced by DNA hypomethylation and TE activation in the liver is mediated by the signaling pathways activated by both cytoplasmic double stranded RNA and DNA and that tnfa mediates cell death as a potential mechanism to eliminate these damaged cells. [ABSTRACT FROM AUTHOR]

Cutaneous leishmaniasis infection affects the immune system, including interlukin-6 (IL-6) and the tumor necrosis factor (TNF-á). In this study, we notice a significant increase in the levels of TNF-á from the normal level in the blood serum of adult male laboratory rats who are experimentally infected with the cutaneous leishmaniasis comparison with control groups, where TNF-á concentrations were (mean / SD) 0.042 ± 0.019 pg / mL recorded, whereas control group recorded 0.018 ± 0.008 pg / mL that is (P <0.05). The resulting TNF-á that consists of mast cells, macrophages and T cells has roles in regulating the immune and inflammatory response and response to programmed cell death in affected tissues. The results showed that there significant differences with statistically cytokine IL-6 in the blood serum of male experimentally with cutaneous leishmaniasis, where the rate of interleukin-6 in the group with CL reached 0.0123 ± 0.009 pg/mL compared to control group 0.015 ± 0.005 pg/mL (P <0.05). Explained that there is a significant strong direct with Pearson Correlation Coefficient between the two elements TNF-á and IL-6, where was recorded (R = 0.612, P-value = 0.061). [ABSTRACT FROM AUTHOR]

Background: The chronic inflammatory skin disease with a strong genetic predisposition and autoimmune pathogenic traits is called Psoriasis. Aim: Study the IL6 (C174G) promoter polymorphisms and correlation with growth factor and TNFA activity in patients with psoriasis in Iraqi population. Subjects and Methods: This study is included 40 subjects (24 males and 16 females) with psoriasis at range of age (11-40) years with mean±SD was (29±11) years and divided into two groups. The control group included 20 subjects matched with age and gender of psoriasis group. GH and TNFA levels were estimated by use of ELISA technique. DNA was extracted from whole blood of both groups and PCR-RFLP was used to perform the genotyping analysis. Results: The results suggesting highly significant differences in GH and TNFA levels between psoriasis and control group (p-value< 0.05). The results showing statistical differences (odd ratio) in CC, CG, and GG between psoriasis and control groups. Conclusion: C174G polymorphism in promoter of IL6 gene with increasing in GH and TNFA levels consider a risk factor for incidence of psoriasis in different ages and genders. [ABSTRACT FROM AUTHOR]

Background: Hemorrhoids are rectoanal venous plexus swelling that causes inflammation, pain, and bleeding. Plants with phenolic compounds are known to improve venous tone and anti-inflammation. Soursop leaves (Annona muricata L.) known contain phenolic compounds and have been used to cure inflammation. However, studies on anti-inflammatory soursop leaves for hemorrhoids are still limited. Objective: This study aims to analyze the effect of Soursop Leaves Ethanol Extract (SLEE) on the histopathological features and expression of COX-2 and TNFa in rectoanal tissue. Method: Swiss mice 20 weeks induced 3 times with 6% croton oil through the anus. SLEE doses of 100, 200, and 400 mg/Kg and aspirin as a positive control were given orally for 7 days. Histopathological examination of the rectoanal tissue of mice was assessed by counting cell necrosis, inflammation, vasodilation, and edema using hematoxylin-eosin. Positive cells expressing COX-2 and TNFa were counted on inflammatory epithelial cells using immunohistochemistry. Results: Administration of SLEE at all doses showed different levels of inflammation, necrosis, vasodilatation and edema in histopathology of rectoanal tissue P <0.00. All three doses of SLEE show significant anti-inflammatory effects on hemorrhoidal tissue. SLEE doses of 200, 400 mg/Kg significantly decreased COX-2 P <0.05 compared to negative controls, and SLEE doses of 100, 200, and 400 mg/Kg significantly decreased TNFa P <0.05 compared to negative controls. Conclusions: SLEE can reduce inflammation and has the potential to be developed as a natural remedy for hemorrhoids. [ABSTRACT FROM AUTHOR]

Identification of genetic predispositions to susceptibility towards bovine tuberculosis (bTB) for the purpose of improving herd resistance to bTB through marker/genomic selection has been one of the thrust areas of research in animal production. Immune response genes, such as Toll Like Receptors (TLRs) which are involved in mycobacterial recognition and activation of innate and adaptive immune responses and Tumor Necrosis Factor alpha (TNFa) which is a vital pro-inflammatory cytokine with pleiotropic roles in immune response that enables mounting of a strong microbicidal action, are potential strong candidates for exploring genetic basis of resistance. Present investigation was aimed at exploring the association of three SNPs (rs43702940, rs68343175 and rs55617317) in TLR1 gene and one SNP (rs109967811) in TNFa gene with susceptibility to bTB infection in cattle. In a case-control population of bTB established using single intradermal tuberculin test, three of the investigated SNPs were found to be polymorphic while rs43702940 revealed monomorphism. SNP loci rs109967811 in TNFa gene was found to be significantly (P < 0.01) associated with susceptibility to bTB in the study population. These findings suggest that SNPs rs109967811 located in exonic region of TNFa can likely serve as a potential marker against bTB infection in cattle upon validation in independent, larger resource population. [ABSTRACT FROM AUTHOR]

Aldehyde dehydrogenase 1 (ALDH1) and hepatocyte nuclear factor 4A (HNF4A) are the putative mammary stem cell markers. Tissue necrosis factor alpha (TNFA) is involved in inflammation-associated carcinogenesis and cell proliferation. In this study, the gene expression profile of ALDH1, HNF4A and TNFA of buffalo mammary tissue using real-time quantitative PCR (RT-qPCR). Analysis of RT-qPCR data revealed that the relative expression (log2 fold change) of ALDH1 and TNFA during mastitis (vs. lactation) was increased (P <.05) by 2.98 and 4.71, respectively. The relative expression (log2 fold change; −7.39) of stem cell marker, HNF4A was decreased (P <.05) during mastitis. Histological analysis of mammary tissue during mastitis showed thickening of stroma and occasionally hyperplasia, predominantly in prepubertal and non-lactating animals. Although, the level of expression of these genes may vary, depending upon the physiological stage of the animals, however expression of ALDH1 and TNFA was high during mastitis. A systematic study on large samples of buffalo mammary tissue with appropriate comparisons needs to be evaluated with these markers for prognosis of buffalo mammary health. [ABSTRACT FROM AUTHOR]

Background: Triple-negative breast cancer is categorized by a lack of hormone receptors, inefficacy of antiestrogen or aromatase inhibitor chemotherapies and greater mortality rates in African American populations. Advancedstage breast tumors have a high concentration of tumor necrosis factor-α (TNFα) throughout the tumor/stroma milieu, prompting sustained release of diverse chemokines (i.e. C-C motif chemokine ligand 2 (CCL2)/CCL5). These potent chemokines can subsequently direct mass infiltration of leukocyte sub-populations to lodge within the tumor, triggering a loss of tumor immune surveillance and subsequent rapid tumor growth. Previously, we demonstrated that in the MDAMB- 231 TNBC cell line, TNFα evoked a rise in immune signaling proteins: CCL2, granulocyte macrophage colonystimulating factor, interleukin (IL)1α, IL6 and inhibitor of nuclear factor kappa-B kinase subunit epsilon (IKBKε) all of which were attenuated by apigenin, a dietary flavonoid found in chamomile and parsley. Materials and Methods: The present work elucidates changes evoked by TNFα in the presence or absence of apigenin by examining the entire transcriptome for mRNA and long intergenic non-coding RNA with Affymetrix Hugene-2.1_ST human microarrays. Differential geneexpression analysis was conducted on 48,226 genes. Results: TNFα caused up-regulation of 75 genes and down-regulation of 10. Of these, apigenin effectively down-regulated 35 of the 75 genes which were up-regulated by TNFα. These findings confirm our previous work, specifically for the TNFα-evoked spike in IL1A vs. untreated controls [+21-fold change (FC), p<0.0001] being attenuated by apigenin in the presence of TNFa (-15 FC vs. TNFα, p<0.0001). Similar trends were seen for apigenin-mediated down-regulation of TNFα-up-regulated transcripts: IKBKE (TNFα: 4.55 FC vs. control, p<0.001; and TNFα plus apigenin: -4.92 FC, p<0.001), CCL2 (2.19 FC, p<0.002; and -2.12 FC, p<0.003), IL6 (3.25 FC, p<0.020; and -2.85 FC, p<0.043) and CSF2 (TNFα +6.04 FC, p<0.001; and -2.36 FC, p<0.007). In addition, these data further establish more than a 65% reduction by apigenin for the following transcripts which were also up-regulated by TNFα: cathepsin S (CTSS), complement C3 (C3), laminin subunit gamma 2 (LAMC2), (TLR2), toll-like receptor 2 G protein-coupled receptor class C group 5 member B (GPRC5B), contactin-associated protein 1 (CNTNAP1), claudin 1 (CLDN1), nuclear factor of activated T-cells 2 (NFATC2), C-X-C motif chemokine ligand 10 (CXCL10), CXCL11, interleukin 1 receptor-associated kinase 3 (IRAK3), nuclear receptor subfamily 3 group C member 2 (NR3C2), interleukin 32 (IL32), IL24, slit guidance ligand 2 (SLIT2), transmembrane protein 132A (TMEM132A), TMEM171, signal transducing adaptor family member 2 (STAP2), mixed lineage kinase domain-like pseudokinase (MLKL), kinase insert domain receptor (KDR), BMP-binding endothelial regulator (BMPER), and kelch-like family member 36 (KLHL36). Conclusion: There is a possible therapeutic role for apigenin in down-regulating diverse genes associated with tumorigenic leukocyte sub-population infiltration by triple-negative breast cancer. The data have been deposited into the Gene Expression Omnibus for public analysis at https://www.ncbi. nlm.nih.gov/geo/query/acc.cgi?acc=GSE120550. [ABSTRACT FROM AUTHOR]

Purpose: There is increased type I interferon signature in psoriasis patients. Interferon-kappa (IFN-κ) is a member of type I interferon family that is constitutively expressed by keratinocytes. In this study, we investigate whether IFN-κ is involved in psoriasis etiology. Patients and methods: Twenty healthy individuals, 20 psoriasis vulgaris patients and 10 atopic dermatitis (AD) were included for this study. Immunohistochemistry staining, normal human epidermal keratinocytes (NHEK) culture, Ca2Cl-induced differentiation, quantitative reverse transcription (qRT-PCR), ELISA and murine experiments were performed. Results: We found IFN-κ protein expression was extremely low in the epidermis of normal skin, but it was significantly increased in the suprabasal layers of epidermal keratinocytes in psoriatic skin lesions. However, its expression in the skin lesions of AD was similar to normal skin. Additionally, IFN-κ protein was detected in sera from psoriasis patients, but not in sera from normal subjects and AD. We further investigated the regulation of IFNk gene expression in NHEK. We found that IFNk was significantly induced by types of nucleic acid pathogen recognition receptor (PRR) agonists in NHEK. While its expression was significantly induced by itself and IFN-γ, it was inhibited by type 2 immunity cytokines IL4 and IL13; other inflammatory cytokines including IL1 super-family members and IL17A did not alter its expression. Addition of recombinant IFN-κ did not affect keratinocytes differentiation. Using the murine experimental model, we demonstrated that subcutaneous administration of recombinant IFN-κ did not increase skin thickness, but significantly increased the transcription of TNFA and IL17A in mice skin. Conclusion: Increased IFN-κ in psoriasis may be caused by injured cells-released nucleic acids, increased IFN-γ and self-activation. Its enhancement may contribute to the etiology of the disease by enhancing TNFA and IL17A gene expression. [ABSTRACT FROM AUTHOR]

This study was aimed at evaluating the possible antiulcer activity of the Nothapodytes foetida in experimental rats. A methanolic root & leaf extract was prepared and antiulcer activity was tested using naproxen induced ulcer models. Omeprazole (30 mg/kg p.o.) was used as the reference drug. Different groups of albino rats of male sex were given two doses (100, 200 mg/kg) of the extract. Methanolic extract of root of N. foetida showed better ulcer inhibition (55.8%) as compared to MEL (36.5%). The results were significant as compared to control (P<0.05). [ABSTRACT FROM AUTHOR]

Background: Literature reports indicate changes in the expression of genes encoding proinflammatory factors are observed as a result of physical exercise. The stress changes caused by high-intensity loads and adaptive changes induced by the planned long-term training are less studied. The aim of this study was to determine the impact of intense anaerobic effort in people adapted to regular trainings and in non-trained persons on the expression levels of the TNFA gene. Material and methods: 50 experienced soccer players and 50 non-trained participants were recruited for the study. Anaerobic capacity was measured by means of the Wingate Anaerobic Test. To evaluate the expression of TNFA gene, a QRT-PCR was applied. Results: A comparison of the TNFA expression profiles between well-trained athletes and non-trained controls revealed that transcript levels were higher in non-trained participants when compared with soccer players in all the studied time points, with the exception of the second post-test; however, this difference was the only one that was statistically insignificant. Conclusions: The TNFA mRNA expression characteristic described in our study indicated a significant downregulation of the TNFA expression observed in the course of time in experienced athletes reflecting molecular adaptation to physical effort caused by long-term training regime. [ABSTRACT FROM AUTHOR]

Psoriasis is a chronic, disfiguring inflammatory skin disease without a single clinical presentation and for which there is no cure, the Pathogenesis is multifactorial and has a bimodal age of onset. It characterized by increase secretion of pro inflammatory cytokines and associated with different HLA alleles in different ethnic groups. To evaluate the association of inheritance of either HLA-CW6, CW7 or CW17 alleleand polymorphic IL1b, IL6 or TNFa gene with the family history of Iraqi patients with type I psoriasis. Current study includes psoriatic group involve 76 patients (type I). After inform consent, a PCR based method (low resolution sequence specific primer. PCR-SSP) used to detect HLA-CW6, CW7 and CW17 allele. And a PCR-SSP for detection of IL1b, IL6 and TNFa polymorphism. There is none statistical association between either CW6, CW7 or CW17 with a positive family history. IL6-C allele, TNFa A\G genotype significantly associated with family history positive group. Among the selected parameters, IL6-C allele and TNFa A\G genotype offer a good chance to develop type I psoriasis among family members with positive family history. [ABSTRACT FROM AUTHOR]

Background: Two current theories regarding the neuroscientific bases of mood disorders involve alterations in glutamatergic neurotransmission and excessive activation of inflammatory pathways. We hypothesized that glutamate (Glu) levels and peripheral inflammatory markers would be associated with cognitive function, in patients with Bipolar Disorder Type II (BP-II), and that such factors would be associated with psychological treatment outcomes. Aims: The primary aim of this study was to explore the relationship between the neurotransmitter Glu, cytokines (CRP, IL_6, and TNFa) and neuropsychological and related functioning. The secondary aim was to assess cognitive functioning as a predictor of poor response to psychological therapy. Methods: Proton magnetic resonance spectroscopy data were acquired from the anterior cingulate cortex (ACC) of 15 participants with BP-II, and 13 healthy controls in a 3T magnetic resonance imaging scanner. The Digit Symbol Task (DST) for processing speed, TMT-B for executive function and Rey Auditory Verbal Learning Test (RAVLT) were administered to assess cognitive domains. Results: There was no significant difference in anterior cingulate Glu, or inflammatory markers between groups. Furthermore, we found no significant difference between groups in any cognitive tests. Scores on the DST were found to be significantly associated with poor response to psychological therapy. Conclusions: This study may highlight an association between neuropsychological dysfunction and treatment outcome in euthymic patients with BP-II. We did not find any association between peripheral inflammatory markers and brain Glu levels. This may have been in part due to the small sample size. [ABSTRACT FROM AUTHOR]

Lifestyle interventions, including exercise and dietary supplementation, can modify DNA methylation and exert health benefits; however, the underlying mechanisms are poorly understood. Here we investigated the impact of acute aerobic exercise and the supplementation of omega-3 polyunsaturated fatty acids (n-3 PUFA) and extra virgin olive oil (EVOO) on global and gene-specific (PPARGC1A, IL6 and TNF) DNA methylation, and DNMT mRNA expression in leukocytes of disease-free individuals. Eight trained male cyclists completed an exercise test before and after a four-week supplementation of n-3 PUFA and EVOO in a double-blind, randomised, repeated measures design. Exercise triggered global hypomethylation (Pre 79.2%; Post 78.7%; p = 0.008), alongside, hypomethylation (Pre 6.9%; Post 6.3%; p < 0.001) and increased mRNA expression of PPARGC1A (p < 0.001). Associations between PPARGC1A methylation and exercise performance were also detected. An interaction between supplement and trial was detected for a single CpG of IL6 indicating increased DNA methylation following n-3 PUFA and decreased methylation following EVOO (p = 0.038). Global and gene-specific DNA methylation associated with markers of inflammation and oxidative stress. The supplementation of EVOO reduced DNMT1 mRNA expression compared to n-3 PUFA supplementation (p = 0.048), whereas, DNMT3a (p = 0.018) and DNMT3b (p = 0.046) mRNA expression were decreased following exercise. In conclusion, we demonstrate that acute exercise and dietary supplementation of n-3 PUFAs and EVOO induce DNA methylation changes in leukocytes, potentially via the modulation of DNMT mRNA expression. Future studies are required to further elucidate the impact of lifestyle interventions on DNA methylation. [ABSTRACT FROM AUTHOR]

Background: This study shows the relationship between host factors and environmental factors in the influence of susceptibility to loss of dental implants. Purpose: The aim of this study was to investigate the association of clinical aspects and tag SNPs of the genes LTA, TNFA, and LTB with dental implant loss. Materials and Methods: The subjects consisted of 244 patients, divided into two groups: control group (C)—163 individuals who did not lose any implants, being in function for at least 6 months; and study group (S)—81 individuals who had lost at least one implant. DNA was collected from saliva, and the genotypes were determined by real time PCR. Univariate and multivariate analysis were employed p < .05. Results: After multivariate analysis, dental implant loss remained associated with the presence of teeth (p = .011), a larger amount of placed implants (p = .001), and allelle C of rs2009658 of the LTA gene (p = .006). For the other tag SNPs of these studied genes, there was no association between the groups C and S with dental implants loss. Conclusion: Presence of teeth, number of placed implants and allele C of rs2009658 of LTA gene were associated with implant loss. [ABSTRACT FROM AUTHOR]

Objectives: The purpose of the present study was to describe our experience with the recombinant Fab' antibody fragment against TNF-a Certolizumab Pegol (CZP) in patients with Behc,et's disease (BD) refractory to standardized therapies and previous biologic agents. Methods: Retrieved data including demographic characteristics, clinical manifestations, and previous treatments were collected in three different specialized Rheumatologic Units in Italy. In order to evaluate disease activity, the BD current activity form (BDCAF) has been used before starting CZP therapy and at each visit during treatment. Results: Thirteen BD patients (mean age 42.6 ± 8.8 years) with a disease duration of 8.80 ± 6.9 years, underwent CZP treatment for 6.92 ± 3.52 months. Six patients (46.15%) experienced a worsening of symptoms after 4.16 ± 1.21 months, whereas a satisfactory response was achieved in seven patients (53.84%) who were still on CZP therapy at the last follow-up visit (after 9.28 ± 3.03 months of treatment). The mean decrease of BDCAF between the first and last visit was 0.308 ± 1.84 without reaching significant difference (mean 8.3 ± 1.3 and 8 ± 2.08, respectively; p= .51). During the whole study period, CZP was well tolerated in all patients except one who developed a generalized cutaneous reaction after the third administration. Conclusions: These results suggest that despite an improvement of clinical manifestations has been observed in more than half of the patients, it is not possible to draw firm conclusions about the effectiveness of CZP in BD and further studies with larger cohorts of patients are warranted. Whether the increase of CZP dosage may ensure a better clinical response remains an unsolved issue that needs to be considered. [ABSTRACT FROM AUTHOR]

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Increased serum concentrations of tumor necrosis factor α (TNFα) and transforming growth factor ß-1 (TGFß-1) in the blood of patients with pancreatic cancer (PC) have previously been demonstrated. In addition, exogenous exposure to these cytokines promotes various cancer cell invasive and cancer stem cell (CSC) phenotypes. However, their importance in pancreatic CSCs remains elusive. In the present study, the effects of TNFα and TGFß-1 on the human PC cell line MiaPaCa-2 were examined. Using flow cytometry, it was revealed that TNFα and TGFß-1 synergistically increase cluster of differentiation (CD) 44v6, CD133 and ATP-binding cassette transporter G2 (ABCG2) expressing populations in adherent tumor cell culture conditions. Furthermore, a similar trend was observed in cells pretreated with these cytokines grown in sphere forming culture conditions. Similar to previous studies, TNFα treatment increased the proportion of epidermal growth factor receptor (EGFR) expressing cells in adherent culture, and this data was further supported by the results of the sphere formation assay, in which the subculture with a high proportion of EGFR expressing cells exhibited the most efficient sphere forming ability. However, the proportion of vascular endothelial growth factor receptor 1 (VEGFR1) expressing cells did not increase upon treatment with these cytokines individually or in combination. This data was subsequently supported by the results of the wound healing assay in which cytokine treatment did not increase the migration of cells. The MTT cell proliferation and cytotoxicity assay revealed that TNFα + TGFß-1 treatment significantly increased cell proliferation and daunorubicin resistance, but not gemcitabine resistance. In conclusion, the data of the current study provide a mechanistic association between TNFα, TGFß-1 and the CSC properties of MiaPaCa-2 cells. In addition, it suggests that targeting TNFα and TGFß-1 is beneficial for improving the therapeutic efficacy of treatments for patients with PC. [ABSTRACT FROM AUTHOR]

Gestational diabetes mellitus (GDM) is a unique form of glucose intolerance, in that it is transient and solely occurs in pregnancy. Pregnancies with GDM are at high risk of developing preeclampsia (PE), a leading cause of fetal and maternal morbidity or mortality. Since PE is associated with excessive activation of circulatory neutrophils and occurrence of neutrophil extracellular traps (NETs) in affected placentae, we examined these features in cases with GDM, as this could be a feature linking the two conditions. Our data indicate that neutrophil activity is indeed altered in GDM, exhibiting pronounced activation and spontaneous generation of NETs by isolated neutrophils in in vitro culture. In this manner, GDM may similarly affect neutrophil behavior and NET formation as witnessed in other forms of diabetes, with the addition of the physiological changes mediated by pregnancy. Since circulatory TNF-α levels are elevated in cases with GDM, a feature also observed in this study, we examined whether this pro-inflammatory cytokine contributed to neutrophil activation. By using infliximab, a clinically utilized TNF-α antagonist, we observed that the pro-NETotic effect of GDM sera was significantly reduced. We also detected pronounced neutrophil infiltrates in placentae from GDM cases. The occurrence of NETs in these tissues is suggested by the extracellular co-localization of citrullinated histones and myeloperoxidase. In addition, elevated neutrophil elastase (NE) mRNA and active enzymatic protein were also detected in such placentae. This latter finding could be important in the context of previous studies in cancer or diabetes model systems, which indicated that NE liberated from infiltrating neutrophils enters surrounding cells, altering cell signaling by the degradation of IRS1. These findings could potentiate the underlying inflammatory response process in GDM and possibly open an avenue for the therapeutic interventions in gestational hyperglycemia. [ABSTRACT FROM AUTHOR]

The objective of the study was to analyze the impact of TNF antagonists (TNFa) on the total cholesterol and triglycerides on ankylosing spondylitis (AS) and psoriatic arthritis (PsA). In this single-centre observational study of AS and PsA patients, differences in triglyceride and total cholesterol levels and frequency of hypertriglyceridemia and hypercholesterolemia at 3 and 6 months were analysed in patients treated and not treated with TNFa. General estimation equations and linear regression analysis were used to investigate associations between disease activity and lipid levels and to identify predictors of change. One hundred fifty-seven patients treated, and 157 not treated with TNFa , were included in the study. A transient increase in cholesterol level from baseline to 3 months in TNFa-treated patients was the only statistically significant effect ( P < 0.001). Persistent percentages of hypertriglyceridemia and hypercholesterolemia from baseline were significantly higher in not treated than in TNFa-treated patients ( P = 0.009 and P = 0.001, respectively). Inverse associations between changes in cholesterol level and Bath Ankylosing Spondylitis Disease Activity Index ( P = 0.011) and CRP ( P < 0.001), but not Disease Activity Score in 28 Joints ( P = 0.095) were found in the whole group. In AS and PsA patients treated with TNFa, mild and transient changes in cholesterol but not in triglyceride levels were associated with changes in disease activity. [ABSTRACT FROM AUTHOR]

We studied the relationship between polymorphisms rs1800629 ( -308G>A), rs28362491 ( -94ins>del), and rs3834129 ( -652ins>del) in the promoter regions of TNFA, NFKB1, and CASP8 genes, respectively, encoding TNF-α, nuclear transcription factor κB1 (NF-κB1), and caspase 8 (CASP8), and the risk and stages of chronic lymphocytic leukemia in ethnic Russians, residents of the Vyatka region of Russia. Allele -308A, genotype -308AA, and -308A genotypes ( -308AA/-308AG) were associated with the risk of this pathology (OR=1.64, 95%CI 1.14-2.37, p=0.007; OR=4.48, 95%CI 1.20-16.80, p=0.02, and OR=1.57, 95%CI 1.05-2.36, p=0.03). In addition, NFKB1 allele -94del and genotype -94del/del were associated with advanced stages of the disease at the time of diagnosis (OR=0.66, 95%CI 0.46-0.97, p=0.03 and OR=0.43, 95%CI 0.20-0.92, p=0.03). These data suggest that -308G>A and - 94ins>del polymorphisms of genes TNFA and NFKB1, respectively, can be involved in the pathogenesis of chronic lymphocytic leukemia. [ABSTRACT FROM AUTHOR]

Condensed-bicyclic 4,6-substituted1,2,4-triazolo-1,3,4-thiadiazole derivatives (CBTT) have been shown to possess a wide spectrum of pharmacological activities. In this study, several novel CBTT derivatives were synthesized and investigated for their possible role as anti-neoplastic agents. The anti-proliferative effect of various CBTT derivatives was analyzed against tumor cell lines by (3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) MTT assay. One of the potential CBTT derivative, 5-(3-(2,3-dichlorophenyl)-[1,2,4]triazolo[3,4- b][1,3,4]thiadiazol-6-yl)flurobenzonitrile (DTTF) was found to be the most potent against cervical cancer SiHa cells and exhibited minimal effect against normal cells. Molecular docking analysis indicated that transcription factor NF-κB was one of the potential molecular targets modulated by DTTF. Specifically, the drug blocked the TNFα-induced phosphorylation of upstream IκBα kinase in a time-dependent manner leading to the suppression of NF-κB activation and nuclear translocation. DTTF also potentiated the apoptotic effect of TNFα, as well as significantly inhibited migration and invasion of tumor cells. Overall, these findings indicate a potential novel role and mechanism(s) of action of DTTF as an anticancer agent against diverse malignancies. [ABSTRACT FROM AUTHOR]

Problem Angiogenic imbalance during pregnancy is associated with immune activation, hypertension, increased T cell infiltration, and neurological insults. Method of Study On gestational day ( GD) 12, timed-pregnant rats were infused with anti-angiogenic factors sFlt-1 and sEndoglin (4.7 and 7 μg/kg) to create HELLP syndrome via mini-osmotic pumps for 8 days, with a subset of these rats having Orencia (2 mg/kg) infused on GD13. On GD19, blood-brain barrier ( BBB) permeability was evaluated via Evan's Blue infusion, blood was collected for T-cell measurements, inflammatory cytokine secretion. Brain tissues were also collected to examine inflammatory cytokine infiltration. Results T-cell attenuation with Orencia decreased circulating CD4+ and CD8+ T cells, circulating tumor necrosis factor alpha ( TNFα) and IL-17, BBB permeability and significantly decreased biochemical evidence of HELLP compared to untreated HELLP rats. Conclusions These data support the hypothesis that T cells have a critical role in contributing to the pathophysiology that is seen in angiogenic imbalance during pregnancy. [ABSTRACT FROM AUTHOR]

Background: The understanding of obsesity-related vascular dysfunction remains controversial mainly because of the diseases associated with vascular injury. Exercise training is known to prevent vascular dysfunction. Using an obesity model without comorbidities, we aimed at investigating the underlying mechanism of vascular dysfunction and how exercise interferes with this process. Methods: High-sugar diet was used to induce obesity in mice. Exercise training was performed 5 days/week. Body weight, energy intake, and adipose tissues were assessed; blood metabolic and hormonal parameters were determined; and serum TNFa was measured. Blood pressure and heart rate were assessed by plethysmography. Changes in aortic isometric tension were recorded on myograph. Western blot was used to analyze protein expression. Nitric oxide (NO) was evaluated using fluorescence microscopy. Antisense oligodeoxynucleotides were used for inducible nitric oxide synthase isoform (iNOS) knockdown. Results: Body weight, fat mass, total cholesterol, low-density lipoprotein cholesterol fraction, insulin, and leptin were higher in the sedentary obese group (SD) than in the sedentary control animals (SS). Exercise training prevented these changes. No difference in glucose tolerance, insulin sensitivity, blood pressure, and heart rate was found. Decreased vascular relaxation and reduced endothelial nitric oxide synthase (eNOS) functioning in the SD group were prevented by exercise. Contractile response to phenylephrine was decreased in the aortas of the wild SD mice, compared with that of the SS group; however, no alteration was noted in the SD iNOS-/- animals. The decreased contractility was endothelium-dependent, and was reverted by iNOS inhibition or iNOS silencing. The aortas from the SD group showed increased basal NO production, serum TNFa, TNF receptor-1, and phospho-IkB. Exercise training attenuated iNOS-dependent reduction in contractile response in high-sugar diet-fed animals, decreased iNOS expression, and increased eNOS expression. Conclusion: Obesity caused endothelium dysfunction, TNFa, and iNOS pathway up-regulation, decreasing vascular contractility in the obese animals. Exercise training was an effective therapy to control iNOS-dependent NO production and to preserve endothelial function in obese individuals. [ABSTRACT FROM AUTHOR]

The host response to pathogens through nuclear factor κB (NF-κB) is an essential defense mechanism for eukaryotic organisms. NF-κB-mediated host responses inhibit bone and other connective tissue synthesis and are thought to affect the transcription of matrix proteins through multiple indirect pathways. We demonstrate that inhibiting NF-κB in osteoblasts increases osteocalcin expression in vivo in mice with periodontal disease. Mutating NF-κB binding sites on osteocalcin (OC) or bone sialoprotein (Bsp) promoters rescues the negative impact of NF-κB on their transcription and that NF-κB can inhibit Wnt-and Bmp-induced OC and Bsp transcription, even when protein synthesis is inhibited, indicating a direct effect of NF-κB. This inhibition depends on p65-p50 NF-κB heterodimer formation and deacetylation by HDAC1 but is not affected by the noncanonical NF-κB pathway. Moreover, NF-κB reduces Runx2 and b-catenin binding to OC/Bsp promoters independently of their nuclear localization. Thus, inflammatory signals stimulate the direct interaction of NF-κB with response elements to inhibit binding of b-catenin and Runx2 binding to nearby consensus sites and reduce expression of matrix proteins. This direct mechanism provides a new explanation for the rapid decrease in new bone formation after inflammation-related NF-κB activation. [ABSTRACT FROM AUTHOR]

Heat-stressed livestock exhibit systemic inflammation, which likely contributes to poor growth and metabolism even when nutritional effects are controlled by pair feeding. Thus, heat stress-induced deficits in growth, metabolism, and well-being may be improved by moderating heightened inflammation. Our objective was to determine whether targeting inflammation by administering anti-inflammatory dexamethasone or fish oil would mitigate blood indicators of inflammation and improve average daily gain (ADG) in heat-stressed lambs. Wether lambs were randomly assigned to 30d of heat stress (40°C, THI=88) or thermoneutral (pair-fed controls; 25°C, THI=70; n=11) conditions. Heat-stressed lambs were randomly assigned to receive no intervention (HS; n=11), oral boluses of fish oil (HS+FO; 360mg; n=11) twice daily, or IM injection of dexamethasone (HS+DEX; 0.15mg/kg; n=11) every 72h. Throughout the study, rectal temperatures and respiration rates were greater (P< 0.05) for HS, HS+DEX, and HS+FO than for controls. Plasma TNFa was greater (P< 0.05) for HS lambs (528±31pg/ml) than for controls (341±28pg/ml), HS+DEX (423±39pg/ml), or HS+FO lambs (376±38pg/ml). Total white blood cells and monocytes were greater (P< 0.05) for HS, HS+DEX, and HS+FO lambs than for controls. Granulocytes and granulocyte:lymphocyte were greater (P< 0.05) for HS and HS+DEX but not HS+FO than for controls. Lymphocytes did not differ among groups and platelets were less (P< 0.05) for HS+FO than for other groups. Blood pH was greater (P< 0.05) for HS, HS+DEX, and HS+FO than for controls early in the study but did not differ by d 30. Blood HCO3 was less (P< 0.05) for HS but not HS+DEX or HS+FO lambs than for controls throughout the study. ADG was reduced (P< 0.05) by 22% for HS lambs but not for HS+DEX or HS+FO lambs compared to controls. These data indicate that supplementing anti-inflammatory agents to chronically heat-stressed lambs improved growth by reducing components of the inflammatory response. [ABSTRACT FROM AUTHOR]

Background: Intracranial aneurysm (IA) is often asymptomatic until the time of rupture resulting in subarachnoid hemorrhage (SAH).There is no precise biochemical or phenotype marker for diagnosis of aneurysm. Environmental risk factors that associate with IA can result in modifying the effect of inherited genetic factors and thereby increase the susceptibility to SAH. In addition subsequent to aneurismal rupture, the nature and quantum of inflammatory response might be critical for repair. Therefore, genetic liability to inflammatory response caused by polymorphisms in cytokine genes might be the common denominator for gene and environment in the development of aneurysm and complications associated with rupture. Methods: Functionally relevant polymorphisms in the pro- and anti-inflammatory cytokine genes IL-1 complex (IL1A, IL1B, and IL1RN), TNFA, IFNG, IL3, IL6, IL12B, IL1RN, TGFB1, IL4, and IL10] were screened in radiologically confirmed 220 IA patients and 250 controls from genetically stratified Malayalam-speaking Dravidian ethnic population of south India. Subgroup analyses with genetic and environmental variables were also carried out. Results: Pro-inflammatory cytokines TNFA rs361525, IFNG rs2069718, and anti-inflammatory cytokine IL10 rs1800871 and rs1800872 were found to be significantly associated with IA, independent of epidemiological factors. TGFB1 rs1800469 polymorphism was observed to be associated with IA through co-modifying factors such as hypertension and gender. Functional prediction of all the associated SNPs of TNFA, IL10, and TGFB1 indicates their potential role in transcriptional regulation. Meta-analysis further reiterates that IL1 gene cluster and IL6 were not associated with IA. Conclusions: The study suggests that chronic exposure to inflammatory response mediated by genetic variants in pro-inflammatory cytokines TNFA and IFNG could be a primary event, while stochastic regulation of IL10 and TGFB1 response mediated by comorbid factors such as hypertension may augment the pathogenesis of IA through vascular matrix degradation. The implication and interaction of these genetic variants under a specific environmental background will help us identify the resultant phenotypic variation in the pathogenesis of intracranial aneurysm. Identifying genetic risk factors for inflammation might also help in understanding and addressing the posttraumatic complications following the aneurismal rupture. [ABSTRACT FROM AUTHOR]

Background and Objective: Sepsis remains a leading cause of death across the world, carrying a mortality rate of 20-50%. Women have been reported to be less likely to suffer from sepsis and to have a lower risk of mortality from sepsis compared to men. The objective of this study was to determine the relationship between gender and mortality in sepsis, and compare cytokine profiles of male and female patients. Methods: This was a prospective case series on 97 patients admitted with sepsis. Clinical and microbiological data was gathered, blood samples were collected for cytokine (IL-10, IL-6 and TNFa) levels and patients were followed up for clinical outcome. Results: There were 54% males and 46% females, with no significant difference of age or comorbids between genders. Respiratory tract infection was the commonest source of sepsis, and was more common in females (60%) compared to males (39%) (p=0.034). Males had a higher mortality (p=0.048, RR 1.73) and plasma IL-6 level(p=0.040) compared to females. Mean IL-6 plasma level was significantly (p<0.01) higher in patients who died vs. who recovered. Conclusion: Our study shows that males with sepsis have a 70% greater mortality rate, and mortality is associated with a higher IL-6 plasma level. [ABSTRACT FROM AUTHOR]

Background: Intracranial aneurysm (IA) is often asymptomatic until the time of rupture resulting in subarachnoid hemorrhage (SAH).There is no precise biochemical or phenotype marker for diagnosis of aneurysm. Environmental risk factors that associate with IA can result in modifying the effect of inherited genetic factors and thereby increase the susceptibility to SAH. In addition subsequent to aneurismal rupture, the nature and quantum of inflammatory response might be critical for repair. Therefore, genetic liability to inflammatory response caused by polymorphisms in cytokine genes might be the common denominator for gene and environment in the development of aneurysm and complications associated with rupture. Methods: Functionally relevant polymorphisms in the pro- and anti-inflammatory cytokine genes IL-1 complex (IL1A, IL1B, and IL1RN), TNFA, IFNG, IL3, IL6, IL12B, IL1RN, TGFB1, IL4, and IL10] were screened in radiologically confirmed 220 IA patients and 250 controls from genetically stratified Malayalam-speaking Dravidian ethnic population of south India. Subgroup analyses with genetic and environmental variables were also carried out. Results: Pro-inflammatory cytokines TNFA rs361525, IFNG rs2069718, and anti-inflammatory cytokine IL10 rs1800871 and rs1800872 were found to be significantly associated with IA, independent of epidemiological factors. TGFB1 rs1800469 polymorphism was observed to be associated with IA through co-modifying factors such as hypertension and gender. Functional prediction of all the associated SNPs of TNFA, IL10, and TGFB1 indicates their potential role in transcriptional regulation. Meta-analysis further reiterates that IL1 gene cluster and IL6 were not associated with IA. Conclusions: The study suggests that chronic exposure to inflammatory response mediated by genetic variants in pro-inflammatory cytokines TNFA and IFNG could be a primary event, while stochastic regulation of IL10 and TGFB1 response mediated by comorbid factors such as hypertension may augment the pathogenesis of IA through vascular matrix degradation. The implication and interaction of these genetic variants under a specific environmental background will help us identify the resultant phenotypic variation in the pathogenesis of intracranial aneurysm. Identifying genetic risk factors for inflammation might also help in understanding and addressing the posttraumatic complications following the aneurismal rupture. [ABSTRACT FROM AUTHOR]

Background: Intracranial aneurysm (IA) is often asymptomatic until the time of rupture resulting in subarachnoid hemorrhage (SAH).There is no precise biochemical or phenotype marker for diagnosis of aneurysm. Environmental risk factors that associate with IA can result in modifying the effect of inherited genetic factors and thereby increase the susceptibility to SAH. In addition subsequent to aneurismal rupture, the nature and quantum of inflammatory response might be critical for repair. Therefore, genetic liability to inflammatory response caused by polymorphisms in cytokine genes might be the common denominator for gene and environment in the development of aneurysm and complications associated with rupture. Methods: Functionally relevant polymorphisms in the pro- and anti-inflammatory cytokine genes IL-1 complex (IL1A, IL1B, and IL1RN), TNFA, IFNG, IL3, IL6, IL12B, IL1RN, TGFB1, IL4, and IL10] were screened in radiologically confirmed 220 IA patients and 250 controls from genetically stratified Malayalam-speaking Dravidian ethnic population of south India. Subgroup analyses with genetic and environmental variables were also carried out. Results: Pro-inflammatory cytokines TNFA rs361525, IFNG rs2069718, and anti-inflammatory cytokine IL10 rs1800871 and rs1800872 were found to be significantly associated with IA, independent of epidemiological factors. TGFB1 rs1800469 polymorphism was observed to be associated with IA through co-modifying factors such as hypertension and gender. Functional prediction of all the associated SNPs of TNFA, IL10, and TGFB1 indicates their potential role in transcriptional regulation. Meta-analysis further reiterates that IL1 gene cluster and IL6 were not associated with IA. Conclusions: The study suggests that chronic exposure to inflammatory response mediated by genetic variants in pro-inflammatory cytokines TNFA and IFNG could be a primary event, while stochastic regulation of IL10 and TGFB1 response mediated by comorbid factors such as hypertension may augment the pathogenesis of IA through vascular matrix degradation. The implication and interaction of these genetic variants under a specific environmental background will help us identify the resultant phenotypic variation in the pathogenesis of intracranial aneurysm. Identifying genetic risk factors for inflammation might also help in understanding and addressing the posttraumatic complications following the aneurismal rupture. [ABSTRACT FROM AUTHOR]

The physiological function of the immune system and the response to therapeutic immunomodulators may be sensitive to combinatorial cytokine micro-environments that shape the responses of specific immune cells. Previous work shows that paracrine cytokines released by virus-infected human dendritic cells (DC) can dictate the maturation state of naïve DCs. To understand the effects of paracrine signaling, we systematically studied the effects of combinations cytokines in this complex mixture in generating an anti-viral state. After naïve DCs were exposed to either IFNβ or to paracrine signaling released by DCs infected by Newcastle disease virus (NDV), microarray analysis revealed a large number of genes that were differently regulated by the DC-secreted paracrine signaling. In order to identify the cytokine mechanisms involved, we identified 20 cytokines secreted by NDV infected DCs for which the corresponding receptor gene is expressed in naïve DCs. By exposing cells to all combinations of 19 cytokines (leave-one-out studies), we identified five cytokines (IFNβ,TNFα, IL-1β,TNFSF15, and IL28) as candidates for regulating DC maturation markers. Subsequent experiments identified IFNβ, TNFα, and IL1β as the major contributors to this anti-viral state. This finding was supported by infection studies in vitro, by T-cell activation studies and by in vivo infection studies in mouse. Combination of cytokines can cause response states in DCs that differ from those achieved by the individual cytokines alone. These results suggest that the cytokine microenvironment may act via a combinatorial code to direct the response state of specific immune cells. Further elucidation of this code may provide insight into responses to infection and neoplasia as well as guide the development of combinatorial cytokine immunomodulation for infectious, autoimmune, and immunosurveillance-related diseases. [ABSTRACT FROM AUTHOR]

Tumor necrosis factor alpha ( TNFA) is an important molecule in inflammatory, infectious, and tumoral processes. Inflammation is one of the early phases in the development of gastric cancer (GC). Therefore, several studies have examined the association of polymorphism in TNFA with gastritis and GC risk. A functional polymorphism, -308G>A (rs1800629), which is located in the promoter of TNFA gene, has been suggested to alter the production of TNF-α and influence cancer risk. To date, a number of studies have been carried out to investigate the relationship between the polymorphism and gastritis or GC susceptibility, but the results were conflicting. To investigate this inconsistency, we performed a meta-analysis of 36 studies for TNFA -308G>A polymorphism to evaluate the effect of TNFA on genetic susceptibility for gastritis and GC. An overall random-effects per-allele odds ratio of 1.16 (95 % confidence interval 1.04-1.29, P = 0.008) was found for the polymorphism. Significant results were also observed using dominant or recessive genetic models. In the subgroup analyses by ethnicity, significant results were found in Caucasians, whereas no significant associations were found among East Asians and other ethnic populations. No associations between the polymorphism and gastritis were observed. In addition, our data indicate that TNFA is involved in GC susceptibility and confers its effect primarily in diffuse type of tumors. Besides, -308G>A polymorphism was found to be significantly associated with both cardiac and noncardiac tumors. This meta-analysis demonstrated that the TNFA -308G>A polymorphism is a risk factor for developing GC, but the associations vary in different ethnic populations. [ABSTRACT FROM AUTHOR]