Increased Concentrations Of TNF-α Research Articles

Curcumin attenuates doxorubicin-induced cardiotoxicity via suppressing oxidative Stress, preventing inflammation and apoptosis: Ultrastructural and computational approaches

Currently, doxorubicin (DOX) is one of the medications commonly used in chemotherapy to treat different types of tumors.Nonetheless, despite being effective in multiple tumors, yet its use is limited owing to its cytotoxic effects, the therapeutic use of DOX has been limited. This work aimed to explore whether curcumin (CMN) can prevents DOX-induced cardiotoxicity in rats. Four groups of rats were created, with the first functioning as a control, while the second group received CMN. DOX alone was administered to the third group, whereas CMN and DOX were administered to the fourth group. Lipid peroxidation assessed as Malondialdehyde (MDA), aspartate aminotransferase (AST), alanine aminotransferase (ALT), oxidative stress markers as catalase (CAT), superoxide dismutase (SOD), and inflammatory markers as tumor necrosis factor-alpha (TNF-α) in heart homogenates, each one was assessed. Heart specimens was investigated histologically and ultrastructurally. Increased, AST, and ALT serum levels, increased MDA levels, decreased SOD and CAT levels, and increased TNF-α concentrations in heart homogenates were all signs of DOX-induced myocardial injury. Histological and ultrastructural examinations revealed vacuoles and larger, swollen mitochondria in the cytoplasm. Furthermore, DOX caused significant changes in the myocardium, most notably nuclei disintegration, myofibrillar loss, and myocyte vacuolization. Using CMN with DOX reduced the harmful consequences of DOX on the myocardium by returning the increased AST and ALT levels to their original levels as compared to the control and reducing them. In cardiac tissue, CMN significantly increased the concentrations of SOD and CAT and significantly decreased the concentrations of MDA and TNF-α. Biochemical and histological studies have demonstrated that CMN has a heart-protective effect that might be related to its antioxidant and anti-inflammatory capabilities.

Serum IL-17 and TNFα as prognostic biomarkers in systemic sclerosis patients: a prospective study

Recent reports have demonstrated that endothelial injury is critical in the pathogenesis of systemic sclerosis (SSc) and is associated with increased levels of circulating inflammatory biomarkers. This study aims to analyze the serum concentrations of selected cytokines and evaluate their relationship with SSc clinics and the long-term course of the disease. This study included 43 SSc patients and 24 matched healthy controls. In both groups, we measured serum levels of inflammatory cytokines related to the inflammatory response, such as tumor necrosis factor (TNF)α, interferon (IFN)γ, interleukin (IL)-4, IL-6, IL-10, and IL-17, and fibroblast activation protein (FAP). Additionally, in SSc patients, we evaluated the presence of four single nucleotide polymorphisms (SNPs) located in the promotor region of the TNFA gene, namely rs361525, rs1800629, rs1799964, and rs1799724, which might be related to increased TNFα concentrations. The main aim consisted of associating inflammatory cytokines with (1) clinical disease characteristics and (2) longitudinal observation of survival and cancer prevalence. SSc patients were characterized by a 17% increase in serum TNFα. There was no other difference in serum cytokines between the studied groups and diffuse vs. limited SSc patients. As expected, evaluated serum cytokines correlated with inflammatory biomarkers (e.g., IL-6 and C-reactive protein). Interestingly, patients with higher IL-17 had decreased left ventricle ejection fraction. During the median 5-year follow-up, we recorded four cases of neoplastic diseases (lung cancer in two cases, squamous cell carcinoma of unknown origin, and breast cancer with concomitant multiple myeloma) and nine deaths. The causes of death included lung cancer (n = 2), renal crisis (n = 1), multiple-organ failure (n = 1), and unknown reasons in five cases. Surprisingly, higher TNFα was associated with an increased cancer prevalence, while elevated IL-17 with death risk in the follow-up. Furthermore, the AG rs361525 genotype referred to higher TNFα levels than GG carriers. Both AG rs361525 and CT rs1799964 genotypes were associated with increased cancer risk. Higher serum concentrations of TNFα characterize the SSc patients, with the highest values associated with cancer. On the other hand, increased IL-17 in peripheral blood might predict poor SSc prognosis. Further research is needed to validate these findings.

Effects of whole-brain radiation therapy on the blood–brain barrier in immunocompetent and immunocompromised mouse models

BackgroundApproximately 20% of all cancer patients will develop brain metastases in their lifespan. The standard of care for patients with multiple brain metastases is whole-brain radiation therapy, which disrupts the blood–brain barrier. Previous studies have shown inflammatory mediators play a role in the radiation-mediated increase in permeability. Our goal was to determine if differential permeability post-radiation occurs between immunocompetent and immunocompromised mice.MethodsWe utilized a commissioned preclinical irradiator to irradiate brains of C57Bl/6J wild-type and athymic nude mice. Acute (3–24 h) effects on blood–brain barrier integrity were evaluated with our in-situ brain perfusion technique and quantitative fluorescent and phosphorescent microscopy. The presence of inflammatory mediators in the brain and serum was determined with a proinflammatory cytokine panel.ResultsBlood–brain barrier integrity and efflux transporter activity were altered in the immunocompetent mice 12 h following irradiation without similar observations in the immunocompromised mice. We observed increased TNF-α concentrations in the serum of wild-type mice immediately post-radiation and nude mice 12 h post-radiation. The brain concentration of CXCL1 was also increased in both mouse strains at the 12-h time point.ConclusionsThe immune response plays a role in the magnitude of blood–brain barrier disruption following irradiation in a time- and size-dependent manner.

Carotenoids as potential inhibitors of TNFα in COVID-19 treatment.

Tumor necrosis factor-alpha (TNF-α) is a multifunctional pro-inflammatory cytokine, responsible for autoimmune and inflammatory disorders. In COVID-19 patients, increased TNF-α concentration may provoke inflammatory cascade and induce the initiation of cytokine storm that may result in fatal pneumonia and acute respiratory distress syndrome (ADRS). Hence, TNFα is assumed to be a promising drug target against cytokine storm in COVID-19 patients. In the present study, we focused on finding novel small molecules that can directly block TNF-α-hTNFR1 (human TNF receptor 1) interaction. In this regards, TNF-α-inhibiting capacity of natural carotenoids was investigated in terms of blocking TNF-α-hTNFR1 interaction in COVID-19 patients with the help of a combination of in silico approaches, based on virtual screening, molecular docking, and molecular dynamics (MD) simulation. A total of 125 carotenoids were selected out of 1204 natural molecules, based on their pharmacokinetics properties and they all met Lipinski's rule of five. Among them, Sorgomol, Strigol and Orobanchol had the most favorable ΔG with the best ADME (absorption, distribution, metabolism, excretion) properties, and were selected for MD simulation studies, which explored the complex stability and the impact of ligands on protein conformation. Our results showed that Sorgomol formed the most hydrogen bonds, resulting in the highest binding energy with lowest RMSD and RMSF, which made it the most appropriate candidate as TNF-α inhibitor. In conclusion, the present study could serve to expand possibilities to develop new therapeutic small molecules against TNF-α.

The effects of mechanical instability on PDGF mediated inflammatory response at early stage of fracture healing under diabetic condition

Background and ObjectiveMechanical stability plays an important role in fracture healing process. Excessive interfragmentary movement will continuously damage the tissue and newly formed capillaries at the fracture site, which leads to overproduction of platelet-derived growth factor (PDGF) that attracts more macrophages into fracture callus, ultimately persistent and enhanced inflammatory response happens. For diabetic condition, the impact of mechanical instability of fracture site on inflammatory response could be further compliciated and the relevant research in this field is relatively limited. MethodsBuilding on previous experimental studies, this study presents a numerical model consisting of a system of reactive-transport equations representing the transport as well as interactions of different cells and cytokines within the fracture callus. The model is initially validated by available experimental data, and then implemented to investigate the role of mechanical stability of fracture site in inflammatory response during early stage of healing. It is assumed that there is an increased release of PDGF due to the rupture of blood vessels resulting from mechanical instability, which leads to increased production of inflammatory cytokines (i.e., TNF-α). The bone healing process under three different conditions were investigated, i.e., mechanically stable condition with normal inflammatory response (Control, Case 1), mechanically unstable condition with normal inflammatory response (Case 2) and mechanically unstable condition with diabetes (Case 3). ResultsMechanical instability can promote the macrophage infiltration and thus induce an enhanced and prolonged inflammatory response, which could impede the MSCs proliferation during the early fracture healing stage (e.g., compared with the control condition, the MSCs concentration in unstable fracture with normal inflammatory response can be reduced by 3.2% and 5.2% on day 2 and day 10 post-fracture, respectively). Under diabetic condition, the mechanical instability of fracture site could lead to a significant increase of TNF-α concentration in fracture callus (Case 3) in comparison to control (Case 1) (e.g., three-fold increase in TNF-α concentration compared to control). In addition, the results show that the mechanical instability affects the cell differentiation and proliferation in fracture callus in a spatially dependent manner, e.g., for diabetic fracture patients, the mechanical instability could potentially decrease the concentration of MSCs, osteoblasts and chondrocytes by around 39%, 30% and 29% in cortical callus, respectively, in comparison to control. ConclusionThe mechanical instability together with diabetic condition can significantly affect the natural resolution of inflammation during early stage of healing by turning acute inflammation into chronic inflammation which is characterized by a continuously upregulated TNF-α pathway.

Selected Mediators of Inflammation in Patients with Acute Ischemic Stroke.

During a stroke, a series of biochemical and metabolic changes occur which eventually lead to the death of cells by necrosis or apoptosis. This is a multi-stage process involving oxidative stress and an inflammatory response from the first signs of occlusion of a blood vessel until the late stages of regeneration and healing of ischemic tissues. The purpose of the research was to assess the concentration of pro-inflammatory cytokines IL-6 and TNF-α in the blood serum of patients with ischemic stroke (AIS) and to investigate their role as new markers in predicting functional prognosis after thrombolytic therapy. The researches have shown that the concentrations of the measured biomarkers were higher compared to the control group. Serum levels of IL-6 and THF-α before the initiation of intravenous thrombolysis were lower in the subgroup of patients with a favourable functional result (mRS: 0–2 pts) compared to the group of patients with an unfavourable functional result (mRS: 3–6 pts). A positive correlation was found between the concentration of IL-6 and TNF-α in patients with AIS during <4.5 h and on one day after the onset of stroke, which means that the concentration of IL-6 increases with the increase in TNF-α concentration. It has also been shown that higher levels of IL-6 in the acute phase of stroke and on the first and seventh days, and TNF-α during onset, were associated with poorer early and late prognosis in patients treated with intravenous thrombolysis. A relationship was found between the level of IL-6 and TNF-α in the subacute AIS and the severity of the neurological deficit. It has been shown that the investigated biomarkers may be a prognostic factor in the treatment of thrombolytic AIS.

Pharmacological inhibition of the mTOR pathway alters phenotype and cytokine expression in bovine monocyte-derived dendritic cells

Epidemiological studies have long demonstrated the association of nutrient status and immune dysfunction in dairy cows. Postpartum dairy cows experiencing a nutrient deficit show a propensity for increased inflammatory response, decreased pathogen clearance, and increased incidence of infectious disease. Studies in cows and other species show that the nutrient sensing mechanistic target of rapamycin (mTOR) signaling pathway could be one potential causal pathway connecting the deficit in nutrient availability and the heightened inflammatory response. Our objective was to investigate the effects of pharmacological mTOR pathway inhibition on phenotype and cytokine expression of bovine monocyte derived dendritic cells (moDC). We differentiated CD14+ monocytes from dairy cows (n = 14) into moDC in the presence or absence of first- or second-generation mTOR inhibitor rapamycin and PP242 (both 100 nM), respectively. On day seven cells were matured with E. coli lipopolysaccharide (LPS, 100 ng/mL) or left unstimulated to represent naïve moDC. Surface expression of CD14, CD40, CD80, and MHCII was measured via flow cytometry. We measured mRNA expression of IL10, IL12A, IL12B, and TNFα by rt-qPCR, and protein concentrations of IL-10 and TFN-α in cell culture supernatants with a bead-based multiplex assay. Cultures from ten cows successfully developed the moDC phenotype in culture without inhibitors, defined as increased surface expression of CD40, CD80, and MHCII compared with naïve moDC. Only data from these cows were considered for the results on effects of mTOR inhibitors. In naïve and mature moDC mTOR inhibition increased MHCII expression compared to controls. In mature moDC, in addition to MHCII, CD80 expression was increased compared with untreated LPS-stimulated controls. Expression of IL12A mRNA was upregulated in mature, mTOR inhibited moDC compared with untreated controls. In cell culture supernatants mTOR inhibition reduced IL-10 and increased TNF-α concentrations in naïve and mature moDCs compared with untreated controls. Overall rapamycin had a more consistent effect on altering phenotype and cytokine expression of moDC than PP242. In summary we observed an increased expression of co-stimulatory molecules and antigen presentation potential in mature moDC differentiated under mTOR inhibition, and a cytokine pattern that would potentially favor a Th1 type response. This study provides novel data indicating a role for mTOR signaling in bovine moDC phenotype and mediator profile. This proof-of-concept study demonstrates the role of the mTOR pathway in shaping the bovine immune response and may help to provide mechanistic insight and opportunities for modulation of the immune response during the nutrient deficit of early lactation.

The protective effect of docosahexaenoic acid on the stomach in Parkinson’s disease induced by MPTP in male C57BL/6 mice

The purpose of this study was to detect gastric changes in Parkinson’s disease induced by 1-methyl-4-phenyl-1.2.3.6.-tetrahydropyridine (MPTP), and to investigate the protective effect of docosahexaenoic acid (DHA) against these changes in mice. The mice were divided into 4 groups (n=10 in per group) as control, DHA, Parkinson and DHA+Parkinson groups. DHA was administered by gavage for 30 days. On the 23rd day of gavage treatment, the animals of the Parkinson and DHA+Parkinson groups were intraperitoneally injected with MPTP. Seven days after the injection of MPTP, their locomotor activity, bradykinesia and rotarod performance were measured. Tyrosine hydroxylase expression in substantia nigra and the apoptotic index, the concentrations of tumor necrosis factor-α and histamine, and the number of mast cells in the stomach were evaluated. Administration of DHA significantly prevented the reduction in motor functions (P&lt;0.001) and nigral TH neurons (P&lt;0.05), and apoptosis (P&lt;0.05), and an increase in TNF-α concentration (P&lt;0.01) in the stomach. An increase in the number of mast cells in the stomach wall was observed in PD (P&lt;0.001). DHA prevented the increase in the number of mast cells (P&lt;0.05) and the histamine level (P&lt;0.01) due to PD. As a result, MPTP administration in mice caused changes in the stomach as well as impairment in motor functions, and DHA was observed to reduce these changes.

Tumor Necrosis Factor-α Inhibits Differentiation of Bone Marrow Mesenchymal Stem Cells into Osteoblasts by Inhibiting Phosphatidylinositol 3-Kinase (PI3K)/Protein Kinase B (AKT) Pathway

Bone marrow mesenchymal stem cells (BMSCs) have the potential for multi-directional differentiation. Tumor necrosis factor-α (TNF-α) plays a role in many diseases. However, the role of TNF-α in the differentiation of BMSCs into osteoblasts remains unclear. Rat-derived BMSCs were divided into normal control group and TNF-α group (5 ng/ml or 10 ng/ml) followed by analysis of BMSCs proliferation by MTT, Caspase3 activity, TNF-α mRNA and serum secretion by Real time PCR and ELISA, ALP activity, Runx2, OP and OC level by Real time PCR and PI3K/AKT signaling protein expression by Western blot. TNF-α significantly promoted the expression of TNF-α mRNA and serum secretion, inhibited cell proliferation, increased Caspase3 and ALP activity, decreased Runx2 and OP expression, and inhibited AKT phosphorylation compared to control (P &lt; 0.05). The inhibition of osteogenic differentiation of BMSCs was more obvious with the increase of TNF-α concentration. TNF-α can inhibit the proliferation of BMSCs, promote apoptosis and inhibit BMSCs osteogenic differentiation via inhibiting the PI3K/AKT pathway.

SINUSOIDAL CELLS AND CYTOKINE RESPONSE IN THE TETRACHLOROMETHANE-INDUCED HEPATOTOXICITY AND AN APPROACH TO ITS CORRECTION

High occurence of liver diseases (toxic, viral hepatitis, liver failure, cirrhosis) requires urgent search of new methods for management of the hepatobiliary diseases. At the present time, the role of immune mechanisms in pathogenesis of diffuse toxic liver damage is not finally clarified. The model of toxic hepatitis induced by carbon tetrachloride (CCl4) is widely known, but this approach allows us to perform complex evaluation and develop the methods for adequate correction of liver disorders in experimental model, which is not always feasible in clinical setting.To design a model of diffuse toxic liver damage, the CCl4 oil solution was used, having been administered intraperitoneally to experimental animals, at a single dose of 50 mg per 100 g body mass. Aiming for correction of toxic liver damage, the injections of aminophthalhydrazide (APH) to experimental animals were carried out intramuscularly at the dose of 2 mg/kg over the terms of experiment. An evaluation of the role of sinusoidal cells (SC) and cytokine production at the local and systemic level were carried out in the model of toxic liver damage caused by CCl4 and its correction by APH treatment. In the course of developing diffuse toxic liver damage induced by CCl4, the production of proinflammatory cytokines TNFα, IL-1α and IL-18 was enhanced at the local level, whereas an increase in TNFα concentration was observed in blood plasma. Following aminophthalhydrazide (APH) administration, the concentrations of proinflammatory cytokines (TNFα and IL-18) decreased at system level, along with locally decreased levels of IL-6 and IFNγ.Changes in the functional state of immunocompetent cells, which include sinusoidal cells (SC), have a significant impact on the development of pathological processes in the liver. The results of our study presume that, over the early periods of toxic impact upon liver tissue, the number of SCs increases both due to influx of blood monocytes and mature macrophages from the peritoneal cavity that enter the injury site directly via mesothelial layer. The SCs provide phagocytosis of damaged hepatocytes and contribute to resolution of the inflammatory process.Modulation of the macrophage activities by APH contributes to increased amounts of SCs at the early stages, and stabilizes their quantities after 2 weeks of APH injections. Change in the numbers of liver SCs during toxic damage affects the production of cytokines. A direct effect of APH upon the SCs may change the production of regulatory factors and compensate the insufficient rate of recovery processes after the toxic damage.

The effects of abamectin on oxidative stress and gene expression in rat liver and brain tissues: Modulation by sesame oil and ascorbic acid

The present work was designed to assess the modulatory effects of sesame oil (SO) and ascorbic acid (AA) on abamectin (ABM)-induced oxidative stress and altered gene expression of hepatic cytochrome P450 2E1 (CYP-2E1), p38 MAPK, and caspase-3 and cerebral P-glycoprotein (Abcb1a receptor). Male rats were distributed into five groups (6 rats/group), receiving distilled water, ABM 2 mg/kg bwt 1/5 LD50 orally for 5 days, ABM + AA 100 mg/kg bwt orally, ABM + SO 5 ml/kg bwt orally, or ABM + SO + AA at the aforementioned doses. Nineteen compounds were identified in the SO sample by GC–MS analysis, including tetradecane,2,6,10-trimethyl, octadecane, 1-hexadecanol,2-methyl, and octadecane,6-methyl. Abamectin significantly upregulated the hepatic CYP-2E1 expression with excess generation of oxidative radicals, as evident by the significant depletion of reduced glutathione and elevation of malondialdehyde concentration (p ≤ 0.05) in rat liver and brain tissues. Further, ABM significantly increased TNF-α concentration, the expression of caspase-3 and p38 MAPK in the liver, as well as p-glycoprotein and GABA-A receptor in the brain. These results were in line with the observed histopathological changes. Sesame oil and/or AA supplementation alleviated ABM-induced cell damage by modulating all tested parameters. In conclusion, ABM induces oxidative stress and increases the expression of CYP-2E1, caspase-3, and p38 MAPK in the liver, as well as P-gp and GABA-A receptor in the brain. These effects could be ameliorated by SO and AA, alone and in combination, probably due to their anti-oxidant, anti-apoptotic, and gene-regulating activities.

Mild traumatic brain injuries with loss of consciousness are associated with increased inflammation and pain in military personnel

Mild traumatic brain injuries (mTBI) are a pervasive concern for military personnel. Determining the impact of injury severity, including loss of consciousness (LOC) may provide important insights into the risk of psychological symptoms and inflammation commonly witnessed in military personnel and veterans following mTBI. US military personnel and veterans were categorized into three groups; TBI with LOC (n = 36), TBI without LOC (n = 25), Controls (n = 82). Participants reported their history of mTBI, psychological symptoms (post-traumatic stress disorder [PTSD] and depression), health-related quality of life (HRQOL), and underwent a blood draw. ANCOVA models which controlled for insomnia status and combat exposure indicated that both mTBI groups (with/without LOC) reported significantly greater depression and PTSD symptoms compared to controls; however, they did not differ from each other. The mTBI with LOC did report greater pain than both controls and mTBI without LOC. The TBI with LOC group also had significantly elevated IL-6 concentrations than both TBI without LOC and control groups. Within the mTBI groups, increased TNFα concentrations were associated with greater PTSD symptoms. These findings indicate that sustaining an mTBI, with or without LOC is detrimental for psychological wellbeing. However, LOC may be involved in perceptions of pain and concentrations of IL-6.

Immunological Response and Match Performance of Professional Tennis Players of Different Age Groups During a Competitive Season.

Kozłowska, M, Żurek, P, Rodziewicz, E, Góral, K, Żmijewski, P, Lipińska, P, Laskowski, R, Walentukiewicz, AK, Antosiewicz, J, and Ziemann, E. Immunological response and match performance of professional tennis players of different age groups during a competitive season. J Strength Cond Res 35(8): 2255-2262, 2021-We aimed to investigate the effect of physical workloads on immunological response, match performance, and iron metabolism in professional tennis players of different age groups throughout the tournament season and to determine the interdependence of vitamin D status and inflammation. Thirty-eight young, male tennis players with a top national ranking (1-25) participated in this study and were assigned to the following age groups: cadets (CG), juniors (JG), and seniors (SG). Blood samples were collected at the beginning, midpoint, and end of the tournament season to assess the proinflammatory cytokine (tumor necrosis factor-alpha [TNF-α]), anti-inflammatory myokines (interleukin [IL]-6 and IL-10), heat shock proteins (HSP70, HSP27), iron metabolism markers, and vitamin D concentrations. The total number of matches (won and lost) at the national and international events was recorded. The IL-6 and IL-10 concentrations significantly increased across all groups in the middle and end of the tournament season (effect large and very likely). The TNF-α concentration was elevated at the end of the season in CG and SG. The increase in TNF-α concentration corresponded with an increase in hepcidin concentration in these groups. The significant increase in HSP27 concentration was only noticed in SG with normal vitamin D concentrations. In JG and SG, a mild seasonal increase in vitamin D concentration was noted, but still it was insufficient. The immunological response was not affected by the number of tennis matches; however, the anti-inflammatory effect was regulated by higher concentrations of vitamin D. Unexpectedly, most tennis players had vitamin D deficiency. Iron status remained unchanged.

Ligands of NOD2 (Muramyl Dipeptide) and TLR4 (LPS) in 24 h after Combined In Vivo Administration Produce a Synergistic Increase in the Content of Multipotent Stromal Cells in the Bone Marrow and Peritoneal Exudate of CBA Mice.

In 24 h after combined administration of ligands of NOD2 (muramyl dipeptide) and TLR4 (LPS) receptors to CBA mice, a synergistic increase (by 10 times compared to the intact control) in cloning efficiency and content of multipotent stromal cells was observed in the bone marrow in comparison with the total effects of their individual administration (by 2.1 and 4.1 times, respectively). A similar effect was also observed in the peritoneal exudate. When ligands were administered simultaneously, the concentration of osteogenic multipotent stromal cells in the bone marrow decreased to a greater extent than in case of individual injections of the ligands, but did not drop below 7% of the control, which is apparently indicative of a decline threshold. In 3 h after simultaneous addition of the ligands in vitro to 12-day primary cultures of mouse bone marrow stromal cells, a synergistic increase in TNFα concentration was observed (32-fold increase from the level of intact control), while IL-10 concentration did not differ from the control, which is indicative of the proinflammatory nature of the process and the absence of immunosuppressive effect. These results suggest that activation of the stromal tissue depends on the intensity of innate immunity reactions.

Relation of Coronary Artery Lumen with Baseline, Post-angioplasty Coronary Circulating Pro-Inflammatory Cytokines in Patients with Coronary Artery Disease

Background: Atherogenic progression in Coronary Artery Disease (CAD) involves a chronic inflammatory process, where local production or release of pro-inflammatory mediators into coronary circulation has a main role. Proinflammatory cytokines IL-6, TNFα and IL1β have been particularly related with the atheroma plaque and CAD severity. Aim: To explore whether characteristics of the coronary artery affected by atheroma plaque were related with coronary circulating pro-inflammatory cytokines and their modifications after angioplasty. Methods: Patients with CAD and stable coronary plaque, submitted to coronary angiography and stenting. Coronary artery lumen diameter at the site of the main atherogenic lesion was measured by intravascular ultrasound, whereas IL-6, TNFα and IL1β concentration in coronary and peripheral blood samples, either before or after angioplasty were determined by multiplexing assay. Baseline distribution of coronary cytokines, or its modification after angioplasty, was evaluated according to the diameter of the lumen of coronary artery (subgroups divided by cutoff value 3.5 mm). Results: Coronary lumen diameter <3.5 mm was related to higher baseline coronary concentrations of IL-1β; as well as to the significant increase in coronary concentrations of TNF-α and IL-6, after angioplasty. Baseline cytokines at peripheral blood did were not modified by coronary lumen diameter; however, coronary lumen <3.5 mm was associated to a peripheral increase in IL-1β, after angioplasty. Conclusion: Coronary lumen diameter, possibly implying plaque characteristics, affects baseline and post-angioplasty coronary concentrations of pro-inflammatory cytokines in patients with CAD.

Does Human Experimental Endotoxemia Impact Negative Cognitions Related to the Self?

A role of inflammatory processes in the pathophysiology of depression is increasingly recognized. Experimental endotoxemia offers an established model to induce transient systemic inflammation in healthy humans, and has been proposed as an experimental paradigm of depression. Indeed, different symptoms of depression can be observed during experimental endotoxemia, including negative mood or dysthymia as key symptoms of depression. Hopelessness and low self-esteem constitute common cognitive symptoms in depression, but have not been specifically assessed during endotoxemia. Thus, we pooled data from healthy volunteers who received low-dose endotoxin (i.e., 0.4 or 0.8 ng/kg lipopolysaccharide, LPS) or placebo in three randomized, controlled studies to investigate the effects of LPS on cognitive schemata related to depression. Validated questionnaires were used to assess self-esteem, hopelessness and the vulnerability factor intolerance of uncertainty after intravenous injection of LPS or placebo. Plasma tumor necrosis factor (TNF)-α and interleukin (IL)-6 were repeatedly assessed, along with self-reported mood. Because not all questionnaires were available from primary studies, data were analyzed in two separate data sets: In data set 1, self-esteem and intolerance of uncertainty were assessed in N = 87 healthy volunteers, who randomly received either 0.4 or 0.8 ng/kg LPS or placebo. In data set 2, hopelessness was measured in N = 59 volunteers who randomly received either LPS (0.8 ng/kg) or placebo. In both data sets, LPS-application led to significant increases in TNF-α and IL-6, reflecting systemic inflammation. Positive mood was significantly decreased in response to LPS, in line with inflammation-induced mood impairment. General self-esteem, intolerance of uncertainty and hopelessness did not differ between LPS- and placebo groups, suggesting that these negative cognitive schemata are not responsive to acute LPS-induced systemic inflammation. Interestingly, LPS-treated volunteers reported significantly lower body-related self-esteem, which was associated with increased TNF-α concentration. Thus, certain aspects of self-esteem related to physical attractiveness and sportiness were reduced. It is conceivable that this effect is primarily related to physical sickness symptoms and reduced physical ability during experimental endotoxemia. With respect to cognitive symptoms of depression, it is conceivable that LPS affects cognitive processes, but not negative cognitive schemata, which are rather based on learning and repeated experiences.

Effects of TNF-α in rheumatoid arthritis via attenuating α1 (I) collagen promoter.

To explore the role of TNF-α in the peripheral blood of patients with rheumatoid arthritis (RA) and its underlying mechanism. 32 patients diagnosed with RA in our hospital from July 2016 to March 2017 were selected in the experimental group. Meanwhile, 32 normal healthy people were selected in the healthy control group and 21 patients with other autoimmune diseases in the same period were selected in the disease control group. Serum samples of the subjects in the experimental group and the control group were collected. The content of serum tumor necrosis factor-α (TNF-α) was detected by enzyme-linked immunosorbent assay (ELISA), and the correlation between TNF-α and RA activity was analyzed. We then constructed rat RA model. The effect of different doses of TNF-α on the RA progression was evaluated by measuring the foot paw thickness of both hind limbs of rats. Fibroblast-like synoviocytes (FLS) were treated with different concentrations of TNF-α cytokine in vitro. Cell counting kit-8 (CCK-8) assay was carried out to detect the cell viability after TNF-α treatment. Serum levels of VEGF (vascular endothelial growth factor) and hydroxyproline were detected. Moreover, the α1 (I) collagen overexpression recombinant was constructed and transfected into MH7A cells. The activation of α1 (I) collagen promoter was reflected by the CAT reporter gene activity. ELISA results showed higher content of TNF-α in the peripheral blood of the experimental group than that of the control group. In the RA rat model, the foot paw thickness of the hind limbs was increased with the increase of TNF-α concentration. CCK-8 and colony formation assay demonstrated that the proliferation of MH7A cells was elevated after TNF-α treatment. Higher levels of VEGF and IL-6 secreted by FLS and decreased collagen synthesis ability of MH7A cells were found after TNF-α treatment. Transfection of the α1 (I) collagen overexpression recombinant in MH7A cells led to the reduced activity of CAT after TNF-α treatment, suggesting that the activation of α1 (I) collagen promoter was inhibited. TNF-α participates in RA by inhibiting the activation of the promoter of α1 (I) collagen, as well as enhancing the secretion of VEGF and IL-6 in MH7A cells.

Neuroprotective effects and underlying mechanism of preconditioning with MK-801 in cerebral ischemia/reperfusion injury in rats induced by cardiac arrest-cardiopulmonary resuscitation

Objective To explore effects of dizocilpine (MK-801) preconditioning on excitatory amino acids and inflammatory response in rats induced by cardiac arrest-cardiopulmonary resuscitation (CA-CPR). Methods 18 male Sprague Dawley (SD) rats were randomly divided into three groups: control group, CA group and CA+ MK-801 group. To establish rat models of CA-CPR and keep samples of serum and specimens of brain tissues for following detection. The injury of neurons was observed by HE staining and expression of N-methyl-D-aspartic acid receptor (NMDAR) in brain tissues was detected by Western blot. The concentrations of interleukin 1 beta (IL-1β) and tumor necrosis factor (TNF)-α in serum were detected by enzyme linked immunosorbent assay (ELISA). Results Neurons in CA group were disorganized, cells shrank, nuclei pyknosis, and cytoplasmic eosinophilia, accompanied by inflammatory cell infiltration. Preconditioning with MK-801 reduced the pathological damage of neuron and degree of macrophage infiltration. The relative expression of NMDAR protein in CA group were significantly higher than that in control group (907.9±24.9 vs 321.6±18.4, P<0.001). Preconditioning with MK-801 significantly decreased the expression of NMDAR in CA+ MK-801 group compared with that in CA group (512.4±21.1 vs 907.9±24.9). The CA group showed significantly increased concentrations of IL-1β and TNF-α than that in control group (P<0.001), and this effect was abolished by preconditioning with MK-801. CA rats treated with MK-801 showed higher concentrations of IL-1β and TNF-α than the control group. Conclusions Cardiac arrest causes pathological injury of neurons, up-regulates expression of NMDAR and aggravates inflammatory response. These results induce the apoptosis of nerve cells. Blocking glutamate receptor with MK-801 can inhibit expression of NMDAR, decrease level of cytokines, down-regulate inflammatory reaction degree therefore to protect the brain. Key words: Dizocilpine maleate/AD; Ischemic preconditioning; Brain ischemia; Reperfusion injury/DT; Receptors, glutamate/ME; Interleukin-1beta/ME; Tumor necrosis factor-alpha/ME; Rats

TNF-α level affects etanercept clearance: TNF-α concentration as a new correction factor of allometric scaling to predict individual etanercept clearances in patients with ankylosing spondylitis.

Etanercept (ETN) is a widely used anti-tumour necrosis factor-α (TNF-α) agent, which relieves the symptoms of ankylosing spondylitis (AS) by binding to TNF-α to inhibit its inflammation effects. In this study, the effect of TNF-α level on ETN clearance (CL) was investigated, and the TNF-α concentration was initially set as a correction factor for allometric scaling to improve the predictions of individual ETN CLs. Individual ETN CLs and TNF-α concentrations in healthy volunteers and patients with AS were determined by performing ETN pharmacokinetic studies in the two cohorts. Accordingly, individual ETN CLs in both healthy volunteers and patients with AS were predicted from data of two animal species using different methods, including simple allometric scaling, scaling with a correction factor of maximum life span potential or brain weight, and scaling with a correction factor of the TNF-α concentration. The accuracies of such predictions were evaluated by the percentage errors. Consequently, increased TNF-α concentration was shown to improve ETN CL, by comparing both ETN CLs and TNF-α concentrations between healthy volunteers and patients with AS. More importantly, better predictions of individual ETN CLs were achieved in patients with AS using allometric scaling with TNF-α concentration as the correction factor. In conclusion, in vivo levels of TNF-α can affect ETN CL, and allometric scaling corrected with the TNF-α concentration can be used to estimate the individual CLs of anti-TNF-α monoclonal antibodies based on preclinical data.

Adiponectin deficiency-induced diabetes increases TNFα and FFA via downregulation of PPARα.

Expression of peroxisome proliferator-activated receptor (PPAR) α was investigated in adiponectin knockout mice to elucidate the relationship between PPARα and adiponectin deficiency-induced diabetes. Adiponectin knockout (Adp−/−) mice were generated by gene targeting. Glucose tolerance test (GTT), insulin tolerance test (ITT), and organ sampling were performed in Adp−/− mice at the age of 10 weeks. PPARα, insulin, triglyceride, free fatty acid (FFA), and tumor necrosis factor α (TNFα) were analyzed from the sampled organs. Adp−/− mice showed impaired glucose tolerance and insulin resistance. Additionally, PPARα levels were decreased and plasma concentration of triglyceride, FFA and TNFα were increased. These data may indicate that insulin resistance in Adp−/− mice is likely caused by an increase in concentrations of TNFα and FFA via downregulation of PPARα.