Tumor Necrosis Factor-alpha Activity Research Articles

The Role of the TLR4-MyD88 Signaling Pathway in the Immune Response of the Selected Scallop Strain “Hongmo No. 1” to Heat Stress

The innate immunity of marine bivalves is challenged upon exposure to heat stress, especially with increases in the frequency and intensity of heat waves. TLR4 serves a classical pattern recognition receptor in recognizing pathogenic microorganisms and activating immune responses. In this study, three genes, HMTLR4, HMMyD88 and HMTRAF6, were characterized as homologs of genes in the TLR4-MyD88 signaling pathway in the selected scallop strain “Hongmo No. 1”. According to RT-PCR, acute heat stress (32 °C) inhibited genes in the TLR4-MyD88 signaling pathway, and LPS stimulation-induced activation of TLR4-MyD88 signal transduction was also negatively affected at 32 °C. ELISA showed LPS-induced tumor necrosis factor alpha (TNF-α) or lysozyme (LZM) activity, but this was independent of temperature. RNA interference (RNAi) confirmed that HMTLR4 silencing suppressed the expression of its downstream gene, whether at 24 °C or at 32 °C. The level of TNF-α and the activity of LZM also decreased after injection with dsRNA, indicating a negative effect on the innate immunity of scallops. Additionally, acute heat stress affected the suppression of downstream gene expression when compared with that at 24 °C, which led us to the hypothesis that heat stress directly influences the downstream targets of HMTLR4. These results enrich the knowledge of scallop immunity under heat stress and can be beneficial for the genetic improvement of new scallop strains with higher thermotolerance.

P583 Infliximab Monitoring in Crohn's Disease and Development of Neural Networks Using Clinical Variables to Predict Disease Activity and Immunogenicity

Abstract Background Infliximab (IFX) is a biological drug that inhibits the action of tumor necrosis factor-alpha (TNFα), a pro-inflammatory cytokine enrolled in the pathogenesis of Crohn's disease (CD). Trough-level drug monitoring (TDM) has been increasingly used in clinical practice to optimize biological therapy and improve precision medicine. Therefore, this study aimed to analyze the serum level of IFX and antidrug antibodies (ADA) in active and in remission CD patients and develop prediction models via neural networks using a combination of clinical variables. Methods Seventy-five CD patients who underwent IFX therapy in the maintenance phase were included. Disease activity was defined by endoscopic and/or radiological criteria, comprising remission (CDR) and active (CDA) groups. Serum IFX levels were measured by ELISA (Promonitor ®) and rapid lateral flow test (Quantum-Blue®). ADA was measured using ELISA (Promonitor ®). For statistical analysis, a non-parametric test was used, with adopted p≤0.05. To create a prediction model, four sets of neural networks were constructed for the following output variables: remission/activity, presence or not of ADA, therapeutic level according to ELISA, and therapeutic level according to the lateral flow test. The neural networks and ROC curves were designed using the Keras package in Python software. The study was approved by the Research Ethics Committee. Results No differences were observed in the IFX level when comparing the CDA and CDR groups in both tests (p> 0.05). There was no statistical difference in IFX levels according to the use of immunosuppressants (IMS) (p>0.05). ADA levels > 5AU/mL were detected in only 11 (14.6%) patients. All patients with positive ADA had infratherapeutic IFX levels in both tests, and 72.7% were on combination therapy with IMS. Of the 4 neural networks developed, two, whose output variables were “remission/activity” and “presence or not of ADA,” showed excellent performance, with AUC ranging from 82% to 92% and 100%, respectively. Conclusion The introduction of IFX monitoring may allow more individualized and precise therapeutic management. Regarding the performance characteristics of the neural networks, an AUC >80% was evident in two of them. Through clinical and non-invasive laboratory variables, disease activity was determined. Furthermore, the finding of combinations of variables that determine the ADA level, and at the same time not having demonstrated good models for IFX serum level measurement, means that the latter continues to be necessary for clinical practice. Otherwise, ADA levels, which indicate immunogenicity, can be predicted by non-invasive clinical variables.

Exploring the chondroitin sulfate nanogel's potential in combating nephrotoxicity induced by cisplatin and doxorubicin—An in-vivo study on rats

In this study, we aim to unveil the potential of itaconyl chondroitin sulfate nanogel (ICSNG) in tackling chronic kidney diseases triggered by the administration of CDDP and doxorubicin (Adriamycin, ADR). To that end, the new drug delivery system (ICSNG) was initially prepared, characterized, and loaded with the target drugs. Thereafter, the in-vivo studies were performed using five equally divided groups of 100 male Sprague-Dawley (SD) rats. Biochemical evaluation and immunohistochemistry studies have revealed the renal toxicity and the ameliorative effects of ICSNG on renal function. When ICSNG-based treatments were contrasted with the CDDP and ADR infected groups, they significantly increased paraoxonase-1 (PON-1), superoxide dismutase (SOD), catalase (CAT) and albumin activity and significantly decreased nitric oxide (NO), tumor necrosis factor alpha (TNF-α), creatinine, urea, and cyclooxygenase-2 (COX-2) activity (p < 0.001). The findings of the current study imply that ICSNG may be able to lessen renal inflammation and damage in chronic kidney disorders brought on by the administration of CDDP and ADR. Interestingly, according to the estimated selectivity indices, the ICSNG-encapsulated drugs have demonstrated superior selectivity for cancer MCF-7 cells, over healthy HSF cells, in comparison to the bare drugs.

Co-administration of thymol and sulfoxaflor impedes the expression of reproductive toxicity in male rats

This study investigated the capability of a co-delivery system of thymol (THY) and sulfoxaflor that can serve to minimize the development of epididymal and testicular injury arise from SFX exposures alone. Forty-eight adult male rats were orally treated by gavage for 28 consecutive days. The rats were divided into six groups comprising control, THY alone (30 mg/kg), low SFX alone (79.4 mg/kg), high SFX alone (205 mg/kg) and co-exposure groups. After euthanasia, the rats epididymal and testicular damage and antioxidant status markers, myeloperoxidase (MPO) activity, levels of nitric oxide, total antioxidant capacity (TAC), total oxidative stress (TOS) and lipid peroxidation (LPO) were analyzed. Levels of tumor necrosis factor alpha (TNF-α), interleukin-1 b (IL-1β) and caspase-3 activity were assessed using ELISA kits. The results revealed that SFX exposure caused a significant (p < 0.05) decrease in the body weight, sperm functional parameters, serum testosterone level with widespread histological abnormalities in a dose-dependent manner. Increased relative organ weights, serum levels of luteinizing hormone (LH) and follicle stimulating hormone (FSH) were observed in low SFX-treated rats. Similarly, the epididymal and testicular myeloperoxidase activity, malondialdehyde (MDA), reactive oxygen species (RONS), tumor necrosis-α, interleukin-1β levels and caspase-3 activity were significant (p < 0.05) increased and a significant (p < 0.05) reduction in antioxidant enzyme activities and reduced glutathione (GSH) were revealed in SFX-treated rats. However, co-treatment of THY with SFX prevented SFX-induced epididymal and testicular toxicities. Thus, thymol protected against potential epididymis and testes alterations elicited by oxido-inflammatory mediators and up regulated antioxidant status.

Effect of amifostine on pulmonary contusion from blunt chest trauma in rats

Purpose: To investigate the efficacy of different doses of amifostine (AMI) and dexamethasone (DXM) on bilateral pulmonary contusion in rats.&#x0D; Methods: Forty-two Sprague Dawley rats were divided into six groups of seven animals each (control, pulmonary contusion (PC), PC + AMI 400 mg/kg, PC + AMI 200 mg/kg, PC + AMI 400 mg/kg + DXM, and PC + DXM-treated groups). RelAssay commercial kit was used to determine total oxidant status (TOS), total antioxidant status (TAS), and oxidative stress index (OSI). Nitric oxide (NO), inducible nitric oxide synthase (iNOS), interleukin-1 beta (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α) activity associated with blunt trauma induced pulmonary damage were determined by enzyme-linked immunosorbent assay (ELISA). Blood gas was determined using a blood gas analyzer, while histopathological examinations were performed on the tissues by hematoxylin and eosin (H &amp; E) staining method.&#x0D; Results: Significant improvement in biochemical parameters and histopathological findings were observed in the groups treated with dexamethasone and high-dose amifostine (400 mg/kg; p &lt; 0.05). However, low-dose amifostine (200 mg/kg) and a combination of dexamethasone with amifostine (400 g/kg) was ineffective in balancing the biochemical changes due to trauma (p &gt; 0.05).&#x0D; Conclusion: High-dose amifostine combined with dexamethasone mitigates trauma-induced damage in rat by preventing the elevation of key inflammatory markers. Further preclinical and clinical studies are required to determine the efficacy of amifostine in humans and to compare its activity with other agents.

Investigation of cardioprotective effect of lercanidipine on doxorubicin-induced cardiotoxicity.

Although doxorubicin (DOX) is an effective anti-neoplastic drug for many types of cancer, particularly dose-related cardiotoxicity limits the use of the drug. In this study, it was aimed to investigate the protective effect of lercanidipine (LRD) against DOX-induced cardiotoxicity. In our study, 40 Wistar albino female rats were randomly divided into 5 groups as control, DOX, LRD 0.5 (DOX + 0.5mg/kg LRD), LRD 1 (DOX + 1mg/kg LRD), and LRD 2 (DOX + 2mg/kg LRD). At the end of the experiment, the rats were sacrificed, and their blood, heart, and endothelial tissues were examined biochemically, histopathologically, immunohistochemically, and genetically. According to our findings, necrosis, tumor necrosis factor alpha activity, vascular endothelial growth factor activity, and oxidative stress were increased in the heart tissues of the DOX group. In addition, DOX treatment caused the deteriorations in biochemical parameters, and levels of autophagy-related proteins, Atg5, Beclin1, and LC3-I/II were detected. Significant dose-related improvements in these findings were observed with LRD treatment. Besides, Atg5, LC3-I/II, and Beclin1 levels evaluated by western blot revealed that LRD exerts a tissue protective effect by regulating autophagy in endothelial tissue. LRD treatment, which is a new-generation calcium channel blocker, showed antioxidant, anti-inflammatory, and anti-apoptotic properties in heart and endothelial tissue in a dose-dependent manner and also showed protective activity by regulating autophagy in endothelial tissue. With studies evaluating these mechanisms in more detail, the protective effects of LRD will be revealed more clearly.

Mechanical Stretch Promotes Invasion of Lung Cancer Cells via Activation of Tumor Necrosis Factor-alpha

Mechanical Stretch Promotes Invasion of Lung Cancer Cells via Activation of Tumor Necrosis Factor-alpha

Immunomodulatory Activity of Begonia Medicinalis Ethanolic Extract in Experimental Animals

Benalu batu (B. medicinalis) is a plant endemic to Central Sulawesi that has been reported to possess anticancer, antioxidant, and antiviral activities. The mechanism of action of these activities is still unclear. This study aimed to evaluate the immunostimulatory effect of ethanol extract of B. medicinalis on an in vivo model by measuring the macrophage phagocytotic activity and cytokine production of tumor necrosis factor-alpha (TNF-α) and interferon-gamma (IFN-γ) on male mice and rats, respectively. The extract was obtained by the maceration method for 3 × 24 h using 70% ethanol. The doses of the extract were 60, 120, and 240 mg/kg body weight (bw). The percentage of macrophage phagocytosis and the TNF-α, and IFN-γ levels were measured on the eighth day, one hour after intraperitoneal injection of Staphylococcus aureus ATCC 25923. The result showed that ethanol extract of B. medicinalis activated macrophage phagocytosis in a dose-dependent manner, with a significant increase in cytokine expression of TNF-α and IFN-γ. The optimal dose was 240 mg/kg bw, with a higher percentage of phagocytic activity and higher levels of TNF-α and IFN-γ than Stimuno® as a positive control and other dosage treatments. This study suggests that B. medicinalis ethanol extract has the effect of an immunomodulator and provides a scientific basis for traditional usage of this herb plant.

Colchicine as adjuvant therapy in COVID-19 patients: a meta-analysis

SARS-CoV-2 infection results in hyperinflammatory responses by activating proinflammatory cytokines and chemokines. Colchicine is an anti-inflammatory drug that reduces superoxide production, tumor necrosis factor alpha (TNF-α) activation, and neutrophil chemotaxis. This study aimed to understand the effect of adjuvant colchicine on mortality in COVID-19 patients. Systematic literature searching was conducted on PubMed, ScienceDirect, Cochrane Library, and medRxiv with keywords colchicine, coronavirus disease, COVID-19, mortality, and SARS-CoV-2. Five randomized controlled studies with 15,779 patients were included. There was no significant difference between the colchicine group and the standard group (OR 1.00 [95% CI 0.91-1.09], p=0.94); invasive mechanical ventilation necessity also did not show a significant difference (OR 0.99 [95% CI 0.83-1.17 p=0.88). There was no significant difference in the incidence of cardiovascular disease (OR 1.11 [95% CI 0.50-2.46], p=0.79), also the incidence of pneumonia was lower in colchicine group (OR 0.68 [95% CI 0.49-0.93], p=0.02), while the incidence of gastrointestinal complaints was higher in colchicine group (OR 2.09 [95% CI 1.84-2.37], p&amp;lt;0.00001). Colchicine as COVID-19 adjuvant therapy did not significantly reduce mortality, the need for invasive mechanical ventilation, and the incidence of cardiovascular disease. Furthermore, the colchicine group had lower pneumonia incidence and higher gastrointestinal complaint incidence.

In vitro inflammatory modulation of bioceramic endodontic sealer in macrophages stimulated by bacterial lipopolysaccharide.

To evaluate the effects of AH Plus (Dentsply), Sealer 26 (Dentsply), and Sealer Plus BC (Produtos Médicos e Odontológicos) on cytotoxicity and inflammation in macrophage cultures exposed to bacterial lipopolysaccharide (LPS). After initial setting, the sealers were conditioned with serum-free culture medium for 24 h (1ml/cm2 ). Macrophages from the RAW 264.7 strain were exposed to sealer extracts in a 1:16 ratio in a culture medium with or without LPS. Cell morphology, viability, mitochondrial activity, oxidative stress and gene expression of interleukin 1β (IL-1β) and tumour necrosis factor-alpha (TNF-α) were evaluated. Data on mitochondrial activity, oxidative stress and TNF-α were analysed using a two-way analysis of variance (anova) test, followed by the Student-Newman-Keuls post-test. IL-1β data were analysed using one-way anova, followed by SNK, and the t-test was used for intragroup comparison. The significance level was set at 5%. In the absence of LPS, only AH Plus and Sealer 26 showed a reduction in cell density, while in the presence of LPS, Sealer 26 had the lowest density compared to the other groups. In terms of mitochondrial activity, at 24 and 48 h, Sealer Plus BC had significantly higher mean values than Sealer 26 and AH Plus (p < .05). Sealer 26 exhibited the lowest levels of oxidative stress and IL-1β and TNF-α expression, regardless of the presence of LPS (p < .05). Although all sealers interfere with the response of macrophages to LPS, contact with epoxy resin-based sealers can impair cell activity in vitro, while bioceramic sealer seems to favour the inflammatory functions of these cells.

Diosmetin alleviates nonylphenol-induced liver damage by improving biochemical, inflammatory, apoptotic and histological profile in rats

Nonylphenol (NP) is an environmental pollutant that is recognized for its hazardous effects on humans and animals. NP has potential to induce oxidative stress that leads to hepatic toxicity. Diosmetin (DIOS) is a naturally occurring bioflavonoid that possesses several biological properties. The current study was designed to ascertain the curative effects of DIOS against NP prompted hepatotoxicity in rats. 32 male albino rats were randomly categorized in 4 groups i.e., control (0.1 % DMSO), NP (50 mg/kg), NP + DIOS (50 mg/kg + 100 mg/kg) and DIOS (100 mg/kg) group. Our results revealed that NP instigated substantial reduction in the antioxidant enzymes activities of catalase (CAT), superoxide dismutase (SOD), glutathione reductase (GSR), glutathione peroxidase (GPx), glutathione S-transferases (GST) and glutathione (GSH). NP administration raised the levels of reactive oxygen species (ROS) as well as the levels of malondialdehyde (MDA). Treatment with DIOS significantly (p < 0.05) recovered activities of antioxidant enzymes, ROS, and TBARS levels. Furthermore, DIOS treatment ameliorated the NP-induced increased level of inflammatory markers i.e., nuclear factor kappa B (NF-κB), interleukin-1 beta (IL-1β), interleukin-6 (IL-6), tumor necrosis factor alpha (TNFα) and cyclooxygenase-2 (COX-2) activity. In addition, DIOS co-treatment also recovered the NP-provoked escalated levels of pro-apoptotic proteins (Bax, caspase-3 and caspase-9) and substantially reduced level of anti-apoptotic protein (Bcl-2) to normal levels. Besides, DIOS treatment recovered the potential histopathological damages in liver tissues. Therefore, DIOS might be an effective therapeutic agent for alleviating NP-induced hepatic toxicity due to its antioxidant, anti-inflammatory and anti-apoptotic potential.

Endothelial dysfunction in patients with obesity

Endothelial dysfunction has been considered in the pathogenesis of obesity widespread in the population. The purpose of this review was to provide updated information about pathogenetic features and markers of endothelial dysfunction in obese patients. We mentioned systemic disorders in obesity, such as oxidative stress, an increase in pro-inflammatory cytokines – tumor necrosis factor alpha, interleukin-6, and arginase activity. We also discussed the role of insulin resistance in the development of endothelial dysfunction, as well as the product of adipose tissue metabolism – monocyte chemoattractant protein-1. The participation of perivascular adipose tissue, hyperoxia of adipose tissue in the regulation of inflammation was considered. We illustrated the influence of atherogenic concentrations of oxidized low-density lipoproteins, the asymmetric dimethyl-L-arginine level on endothelial function. Changes in laboratory parameters were analyzed: endothelin-1, levels of microalbuminuria, homocysteine and uric acid. We also described cytological (circulating vascular cells, endothelial microparticles) and instrumental (endothelium-dependent vasodilation, peripheral arterial tonometry, intima-media complex thickness of the common carotid artery, ultrasound kidneys examination with duplex scanning of the renal arteries) methods for assessing endothelial function. Factors that influence the risk of cardiovascular complications were arterial hypertension and arterial stiffness, high levels of low-density lipoprotein and triglycerides, reduced physical activity. The determination of endothelial function in patients with obesity can be important for predicting the pathology of the cardiovascular system. Information on the assessment of markers of endothelial dysfunction in such patients may expand the possibilities of early diagnosis and prevention of cardiovascular complications.

The Acute Effect Of A Laboratory Shame Induction Protocol On Endothelial Function

Shame is a self-conscious emotion that arises when one internalizes social devaluations from others. Increased shame in a laboratory setting is associated with increased cortisol and tumor necrosis factor alpha activity, however, no studies have investigated the acute effects of shame on important indices of cardiovascular disease risk such as endothelial function. The endothelium is a single layer of cells which lines the inside of all arteries and acts as a vasoprotective and vasoactive agent by inhibiting the development of atherosclerosis and adjusting vessel diameter in response to changes in blood flow associated shear stress (flow-mediated dilation). PURPOSE: The objective of this study was to examine the impact of a shame induction protocol on endothelial function. METHODS: Fifteen, young (23 ± 2 years), healthy participants (n = 7 men, n = 8 women) completed both a 20-min written shame induction and control protocol on two different experimental days. Pre- and post-protocol we assessed: 1) Endothelial function via a standard brachial artery reactive hyperemia flow-mediated dilation (RH-FMD) test which was characterized as the peak % and absolute change in diameter following release of 5 min of forearm occlusion, and; 2) Perceived shame via the Experiential Shame Scale (ESS). RESULTS: Shame increased in response to the shame induction protocol (pre: 2.9 ± 0.6 vs. post: 3.7 ± .5, p < 0.001) but not the control protocol (pre: 3.0 ± 0.5 vs. post: 2.8 ± 0.5, p = 0.15). %RH-FMD significantly decreased in response to the shame protocol (pre: 4.8 ± 1.9 vs. post: 3.2 ± 1.6, p < 0.001) but not the control protocol (4.2 ± 1.8 vs. post: 3.8 ± 1.5, p = 0.45). Covariation of the shear stress stimulus for RH-FMD did not alter the RH-FMD results. Increased shame was significantly associated with decreased absolute RH-FMD (r = -0.37, p = 0.046). CONCLUSIONS: The shame induction protocol caused a significant increase in shame and reduction in RH-FMD. This suggests that temporary increases in shame cause transient endothelial dysfunction which, if chronically repeated, could manifest as reduced vasoprotection against atherosclerosis. Supported by a Natural Sciences and Engineering Research Council of Canada (NSERC) discovery grant.

Sprayable nanomicelle hydrogels and inflammatory bowel disease patient cell chips for development of intestinal lesion-specific therapy.

All-in-one treatments represent a paradigm shift in future medicine. For example, inflammatory bowel disease (IBD) is mainly diagnosed by endoscopy, which could be applied for not only on-site monitoring but also the intestinal lesion-targeted spray of injectable hydrogels. Furthermore, molecular conjugation to the hydrogels would program both lesion-specific adhesion and drug-free therapy. This study validated this concept of all-in-one treatment by first utilizing a well-known injectable hydrogel that underwent efficient solution-to-gel transition and nanomicelle formation as a translatable component. These properties enabled spraying of the hydrogel onto the intestinal walls during endoscopy. Next, peptide conjugation to the hydrogel guided endoscopic monitoring of IBD progress upon adhesive gelation with subsequent moisturization of inflammatory lesions, specifically by nanomicelles. The peptide was designed to mimic the major component that mediates intestinal interaction with Bacillus subtilis flagellin during IBD initiation. Hence, the peptide-guided efficient adhesion of the hydrogel nanomicelles onto Toll-like receptor 5 (TLR5) as the main target of flagellin binding and Notch-1. The peptide binding potently suppressed inflammatory signaling without drug loading, where TLR5 and Notch-1 operated collaboratively through downstream actions of tumor necrosis factor-alpha. The results were produced using a human colorectal cell line, clinical IBD patient cells, gut-on-a-chip, a mouse IBD model, and pig experiments to validate the translational utility.

Thymol Reduces Hepatorenal Oxidative Stress, Inflammation and Caspase-3#xd; Activation in Rats Exposed to Indomethacin

ABSTRACT Indomethacin (IND) is a non-steroidal anti-inflammatory drug with many pharmacological benefits and multi-organ toxicities. Thymol (THY) is a natural phenolic monoterpenoid with many biological properties. However, there is scarcity of information on its potential on IND-induced hepatorenal damage in rats. This study investigated the effect of THY on IND-induced hepatorenal damage in rats. The four experimental groups contain control, IND alone (5 mg/kg), THY alone (250 mg/kg) and co-treated group that were treated orally for 21 consecutive days. Twenty four hour after treatments, rats were sacrificed and markers of hepatorenal damage (ALT, ALP, AST, G6PDH, GGT, BIL, CHOL, GLDH, LDH, MDH, SDH, creatinine, urea, uric acid, cystatin-C and electrolytes), antioxidant status markers, myeloperoxidase (MPO) activity, nitric oxide (NO), lipid peroxidation (LPO), tumor necrosis factor alpha (TNF-α), interleukin-1β (IL-1β) levels and caspase-3 activity were evaluated. IND increased hepatorenal toxicity, inflammatory and apoptotic markers and decreased antioxidant status. Co-administration of IND with THY significantly decreased hepatorenal damage biomarkers improved the antioxidant status and reduced the MPO activity, LPO, NO, TNF-α, IL-1β levels and caspase-3 activity in the liver and kidney of rats. In conclusion, THY mitigates against IND-induced oxidative stress, inflammation and caspase-3 activation in the liver and kidney of the rats.

Adiponectin in normal and atherosclerotic intima of human aorta

Adiponectin (AN) is a protein synthesized by adipocytes that has regulatory effects on lipid and lipoprotein metabolism, increases tissue sensitivity to insulin, and modulates endothelial functions and inflammatory response. However, its involvement in the processes of atherogenesis remains poorly understood. To determine the localization and sources of AN in atherosclerotic and normal human aortic intima. Immunohistochemical study was performed on sections of atherosclerotic and normal human aorta obtained during autopsy. Reverse transcription real-time PCR was performed using biopsies of para-aortic and abdominal adipose tissue, intima-media of the thoracic aorta, atherosclerotic plaques of the human carotid and femoral arteries, as well as on endothelial cells isolated from the human thoracic aorta. Transendothelial transport of AN was evaluated in a two-chamber model using a monolayer of human endothelial cell hybridoma EA.Hy926. It has been established that AN is present in atherosclerotic but not in normal human aortic intima. At the same time, AN ADIPOQ mRNA was not detected either in the intima media of the human aorta, nor in isolated endothelial cells of the aorta, nor in cells of atherosclerotic plaques of the carotid and femoral arteries. AN slowly penetrated the endothelial monolayer in vitro, but this transport was significantly enhanced by the action of tumor necrosis factor-alpha (TNFa). Obtained data indicate that AN is present in atherosclerotic but not in normal aortic intima. We assume that AN is not synthesized by the cells of normal and atherosclerotic arterial walls, but permeates from the plasma. Transendothelial transport of AN, like many other plasma proteins, is activated during the development of atherosclerotic lesions, apparently under the action of pro-inflammatory cytokines, in particular, TNFα.

Effect of TNF-alpha on endometrial glucose transporter-4 expression in patients with polycystic ovary syndrome through nuclear factor-kappa B signaling pathway activation.

The present study aimed to investigate the possible mechanism of action of tumor necrosis factor-alpha (TNF-α) in endometrial glucose transporter-4 (GLUT-4) expression regulation by detecting the expression levels of endometrial inflammatory factors and GLUT-4 in patients with polycystic ovary syndrome (PCOS). A total of 140 patients were included in this study and divided into four groups: the PCOS group, the obesity + PCOS group, the normal group, and the obesity group (n = 35 each). The general clinical data of all patients were collected, and their expression levels of TNF-α, nuclear factor kappa B p65 (NF-κBp65), and GLUT-4 in the endometrium were tested via immunohistochemistry. Endometrial stromal cells were cultured in vitro and treated with TNF-α or pyrrolidine dithiocarbamate (PDTC) + TNF-α, and the expression levels of NF-κBp65, phospho-NF-κBp65 (p-NF-κBp65), and GLUT-4 were tested using Western blotting (WB) before and after treatment. As a result, we got: 1) Compared with the normal group, the abundance of the protein for TNF-α and NF-κBp65 in the endometrium of the patients with PCOS was elevated, while the expression level of GLUT-4 was decreased; the difference was statistically different (P < 0.05). The comparison between the obesity + PCOS group and the PCOS group yielded the same results. 2) According to the WB results, compared with the normal group, the abundance of the protein for endometrial GLUT-4 was decreased in the PCOS group, and the expression levels of p-NF-κBp65 and NF-κBp65 were increased in the obesity + PCOS group; the differences were statistically different (P < 0.05). The addition of TNF-α could decrease the abundance of the protein for GLUT-4 and increase the abundance of the protein for p-NF-κBp65. After treatment with PDTC + TNF-α, the abundance of the protein for p-NF-κBp65 decreased and GLUT-4 increased compared with the TNF-α group; these values were close to those of the control group. We concluded that the abundance of the proteins for local inflammatory factors in the endometrial cells of patients with PCOS was increased, indicating that TNF-α could affect the expression of endometrial GLUT-4 in such patients by activating the p-NF-κBp65 signaling pathway.

Sitafloxacin reduces tumor necrosis factor alpha (TNF\u03b1) converting enzyme (TACE) phosphorylation and activity to inhibit TNF\u03b1 release from lipopolysaccharide-stimulated THP-1 cells

Sepsis is a systemic reaction to an infection and resulting in excessive production of inflammatory cytokines and chemokines. It sometimes results in septic shock. The present study aimed to identify quinolone antibiotics that can reduce tumor necrosis factor alpha (TNFα) production and to elucidate mechanisms underlying inhibition of TNFα production. We identified quinolone antibiotics reduced TNFα production in lipopolysaccharide (LPS)-stimulated THP-1 cells. Sitafloxacin (STFX) is a broad-spectrum antibiotic of the quinolone class. STFX effectively suppressed TNFα production in LPS-stimulated THP-1 cells in a dose-dependent manner and increased extracellular signal-regulated kinase (ERK) phosphorylation. The percentage of intracellular TNFα increased in LPS-stimulated cells with STFX compared with that in LPS-stimulated cells. TNFα converting enzyme (TACE) released TNFα from the cells, and STFX suppressed TACE phosphorylation and activity. To conclude, one of the mechanisms underlying inhibition of TNFα production in LPS-stimulated THP-1 cells treated with STFX is the inhibition of TNFα release from cells via the suppression of TACE phosphorylation and activity. STFX may kill bacteria and suppress inflammation. Therefore, it can be effective for sepsis treatment.

Manganese mitigates against hepatorenal oxidative stress, inflammation and caspase-3 activation in rats exposed to hexachlorobenzene

The present study investigated the individual and collective effect of organochlorinated fungicide hexachlorobenzene (HCB) and manganese (Mn), a metal, on the hepatorenal function in adult rats. Rats were divided into four groups of rats comprising of control, HCB alone (15 mg/kg), Mn alone (10 mg/kg) and co-exposure group that were orally treated for 25 consecutive days. After sacrifice, hepatorenal damage and antioxidant status markers, myeloperoxidase (MPO) activity, levels of nitric oxide, total antioxidant capacity (TAC), total oxidative stress (TOS) and lipid peroxidation (LPO) were analyzed spectrophotometrically. Levels of tumor necrosis factor alpha (TNF-α), interleukin-1 β (IL-1β) and caspase-3 activity were assessed using ELISA. Results revealed that the HCB administration significantly (p < 0.05) increased the biomarkers of hepatorenal toxicity, decreased the antioxidant status and TAC, raised the levels of TOS and LPO as well as increased the levels of TNF-α, IL-1β and caspase-3 activity. Rats co-exposed to HCB and Mn showed decreased biomarkers of hepatorenal damage, increased antioxidant status and TAC with simultaneous reduction in the levels of TOS and LPO significantly (p < 0.05). Furthermore, the increased levels of TNF-α, IL-1β and caspase-3 activity were significantly (p < 0.05) reduced in the liver and kidney of rats’ co-expose to HCB and Mn. Histological examination showed that damages induced by HCB were assuaged in rats co-treated with HCB and Mn. In conclusion, the results demonstrated that co-treatment of HCB and Mn in rats’ alleviated HCB-induced oxidative stress, inflammation and caspase-3 activation in the liver and kidney of the rats.

Could omega-3 fatty acids preserve endothelial function in a rat model of rheumatoid arthritis?

Could omega-3 fatty acids preserve endothelial function in a rat model of rheumatoid arthritis? Background: Endothelial dysfunction is claimed to be the cause of increased risk for cardiovascular diseases in rheumatoid arthritis (RA) patients. Omega-3 fatty acids is a promising drug in this field; however, its exact effects on endothelial functions are not fully understood. Aim of the work: This study aimed to evaluate the effect of omega-3 fatty acids on endothelial reactivity and some markers of endothelial dysfunction [Vascular cell adhesion molecule-1 (VCAM-1), tumour necrosis factor alpha (TNF-α), Malondialdehyde (MDA) and NOS activity] in a rat model of rheumatoid arthritis. Material & methods: Thirty male rats were divided into 3 groups (control, untreated RA, and RA group with omega-3 supplementation). RA induction was done by intradermal injection of heat-killed Mycobacterium butyricum and was confirmed by clinical signs of arthritis on day 11. In the treated group, omega-3 was given daily via gastric gavage starting from day 11 until the end of the study. The study duration was 30 days for all groups starting from the day of induction. At the end of the study, rats were sacrificed, blood samples were collected for VACM-1, TNF-α, MDA and nitrite measurement and thoracic aortae were taken to test vascular reactivity. Results: All markers increased while vascular reactivity decreased significantly after RA induction. Omega-3 treatment significantly decreased all biochemical markers and restored normal vascular reactivity in the treated group.