Significant Reduction In TNF-α Levels Research Articles

BET-inhibitor DYB-41 reduces pulmonary inflammation and local and systemic cytokine levels in LPS-induced acute respiratory distress syndrome: an experimental rodent study

BackgroundAcute respiratory distress syndrome (ARDS) is a form of respiratory failure stemming from various underlying conditions that ultimately lead to inflammation and lung fibrosis. Bromodomain and Extra-Terminal motif (BET) inhibitors are a class of medications that selectively bind to the bromodomains of BET motif proteins, effectively reducing inflammation. However, the use of BET inhibitors in ARDS treatment has not been previously investigated. In our study, we induced ARDS in rats using endotoxin and administered a BET inhibitor. We evaluated the outcomes by examining inflammation markers and lung histopathology.ResultsNine animals received treatment, while 12 served as controls. In the lung tissue of treated animals, we observed a significant reduction in TNFα levels (549 [149–977] pg/mg vs. 3010 [396–5529] pg/mg; p = 0.009) and IL-1β levels (447 [369–580] pg/mg vs. 662 [523–924] pg/mg; p = 0.012), although IL-6 and IL-10 levels showed no significant differences. In the blood, treated animals exhibited a reduced TNFα level (25 [25–424] pg/ml vs. 900 [285–1744] pg/ml, p = 0.016), but IL-1β levels were significantly higher (1254 [435–2474] pg/ml vs. 384 [213–907] pg/ml, p = 0.049). No differences were observed in IL-6 and IL-10 levels. There were no significant variations in lung tissue levels of TGF-β, SP-D, or RAGE. Histopathological analysis revealed substantial damage, with notably less perivascular edema (3 vs 2; p = 0.0046) and visually more inflammatory cells. However, two semi-quantitative histopathologic scoring systems did not indicate significant differences.ConclusionsThese preliminary findings suggest a potential beneficial effect of BET inhibitors in the treatment of acute lung injury and ARDS. Further validation and replication of these results with a larger cohort of animals, in diverse models, and using different BET inhibitors are needed to explore their clinical implications.

OP27 Oxalyl-CoA decarboxylase is a major and specific virulence factor for Adherent Invasive Escherichia coli

Abstract Background Adherent Invasive E. coli (AIEC) strains are found in one-third of patients with ileal Crohn’s disease (CD). To date, the bacterial genes involved in AIEC survival in the inflammatory environment are still unclear. Here, we systematically identify the genes of AIEC required for gut colonization and survival under the inflammatory conditions present in a mouse model of IBD. Methods We performed a transposon sequencing (TnSeq) approach using the laboratory strain E. coli K12 MG1655 and the AIEC strain LF82. We created two saturated Tn mutant libraries (3x105 mutant per bank) and gavaged them to mice with and without dextran-sodium sulfate (DSS)-induced colitis. We screened for essential genes for each bacterium in both conditions in the Cecum, Colon, Ileum and Jejunum. Results After High-throughput sequencing, we identified oxc gene, encoding for the oxalyl-CoA decarboxylase enzyme, as crucial for the survival of LF82 but not MG1655 in the whole gastrointestinal tract in colitis setting. To confirm our TnSeq results, the effect of oxc isogenic mutant (∆oxc) and complemented strains of LF82 and MG1655 was tested. The inflammation severity was exacerbated in mice colonized with LF82WT or the complemented strain compared to LF82∆oxc. LF82∆oxc strain load decreased after colitis induction while the LF82WT and the complemented strain persisted. In a competition between LF82 WT and ∆oxc, the WT strain was able to outcompete the ∆oxc strain. This altered ability of LF82∆oxc to colonize the gut was associated with decreased bacterial motility and flagella expression. In vitro, we found a decreased resistance of different AIEC strains to oxidative stress and acidic pH compared to a collection of commensal E. coli strains. This difference was abolished in all the ∆oxc AIEC strains we built and tested, demonstrating a crucial role for this gene in the tolerance to oxidative and acidic stress. Finally, lack of oxc also caused a reduction in survival into RAW264.7 macrophages, and an altered pro-inflammatory response of the macrophage, with a significant reduction of TNF-α levels. Conclusion oxc plays a major role in vitro and in vivo for AIEC strains but not for laboratory or commensal strains. Further studies to (i) fully explore this role and (ii) evaluate Oxc as a therapeutic target are currently under investigation.

Design, synthesis and biological evaluation of newly triazolo-quinoxaline based potential immunomodulatory anticancer molecules

It is evident that cancer is a serious disease with a growing incidence and high mortality rate. Based on the CRBN binding properties of glutarimide moiety of thalidomide molecule, and triazolo-quinoxaline cytotoxic activity, we decided to innovate new triazolo-quinoxaline based molecules hybridized with glutarimide moiety for potential immunomodulatory anticancer activity. The biological data revealed that 4-oxotriazoloquinoxaline based candidate (15) was of particular antiproliferative significance compared to doxorubicin. It showed IC50 of 9.81 ± 0.7, 15.49 ± 1.2, and 10.09 ± 0.9 μM against hepatocellular (HepG2), prostate cancer (PC3), and breast cancer (MCF-7), respectively. Meanwhile, doxorubicin revealed IC50 of 14.61 ± 1.1, 16.32 ± 1.1, and 12.41 ± 0.74 μM, respectively. Moreover, compound 15 was comparable to thalidomide in elevating the levels of caspase-8 by about 8 folds in HepG-2 cells. Similarly, it showed almost the same effect as thalidomide in reducing VEGF levels in HepG-2 cells. Whereas it was superior to thalidomide in decreasing the levels of NF-κB P65 in HepG-2 cells from 278.1 pg/mL to 82.4 pg/mL compared to 110.5 pg/mL reported for thalidomide. At the same time, 15 and thalidomide were comparable in their significant reduction of TNF-α levels in HepG-2 cells by about one third. Furthermore, molecular docking studies demonstrated the binding properties of the new candidates to CRBN. Accordingly, this work suggests the significance of the triazolo-quinoxaline derivatives carrying glutarimide moiety, in particular compound 15, that showed considerable data for further consideration in order to develop new effective anticancer drugs.

Safety evaluation and effects of cascara pulp Gayo Arabica coffee cream as anti-photoaging in animal model.

Prolonged sunlight and ultraviolet (UV) exposure causes premature skin aging called photoaging and coffee-derived topical antioxidants may help to reduce this process. Since a significant amount of antioxidant-rich cascara pulp are wasted in coffee processing, this study aimed to evaluate the safety of cascara extract cream of Gayo Arabica coffee pulp (CECGACP) as anti-photoaging in male Wistar rats (Rattus norvegicus) by assessing the skin primary irritation index (PII), skin macroscopic changes and the level of tumor necrosis factor-alpha (TNF-α). Twenty-five rats were randomly divided into five different groups: negative control (base cream only), positive control containing L-ascorbic acid 3%, and three treatment groups treated with cream containing 5%, 7.5% and 10% of CECGACP. The CECGACP was extracted, formulated into cream as a topical treatment and applied on the backs of the rats two times a day, once before the UV exposure and four hours after the exposure. After four weeks, the skins were macroscopically examined, and the TNF-α levels were measured. The PII was assessed after applying the cream 24 hours before UX exposure. Our data suggested that CECGACP was considered safe because there were no erythema and edema formation on the skin of the rats with PII score of 0 (classified as no irritation or negligible). After UV exposure, all rats had visible wrinkles and erythema on the skin in particular in the first week. After administration of CECGACP, both wrinkles and erythema were decreased. The levels of TNF-α varied from 0.15±0.02 ng/mL in the negative control and CECGACP 7.5% rat groups to 0.19±0.03 in the positive control group; however, there was no significant difference among all the groups. Our study suggests that CECGACP is safe to use in Wistar rats and able to reduce the erythema and edema due to UV exposure. However, the application of CECGACP does not provide a significant reduction of TNF-α levels.

Effects of vitamin D supplementation on inflammatory response in patients with cancer and precancerous lesions: Systematic review and meta-analysis of randomized trials

Inflammation plays a key role in tumor development and progression. Vitamin D has potential tumor suppressing effects through modulation of inflammatory processes. The aim of this systematic review and meta-analysis of randomized controlled trials (RCTs) was to summarize and evaluate the effects of vitamin D3 supplementation (VID3S) on serum inflammatory biomarkers among patients with cancer or pre-cancerous lesions. We searched PubMed, Web of Science and Cochrane databases until November 2022. The effects of VID3S were estimated from pooled standardized mean differences (SMDs) with their 95% confidence intervals (CIs) for inflammatory biomarker follow-up levels between intervention and control groups. Meta-analysis of eight RCTs (total of 592 patients with cancer or pre-cancerous conditions) showed that VID3S significantly lowered levels of serum tumor necrosis factor (TNF)-α (SMD [95%CI]:-1.65 [-3.07;-0.24]). VID3S also resulted in statistically non-significantly lower serum levels of interleukin (IL)-6 (SMD [95%CI]:-0.83, [-1.78; 0.13]) and C-reactive protein (CRP) (SMD [95%CI]:-0.09, [-0.35; 0.16]), whereas IL-10 levels were unaltered (SMD [95%CI]:-0.00, [-0.50; 0.49]). Our study shows evidence of a significant reduction of TNF-α levels by VID3S for patients with cancer or precancerous lesions. Patients with cancer or precancerous lesions may benefit from personalized VID3S in suppressing tumour-promoting inflammatory response. CRD42022295694.

Efficacy of convalescent plasma therapy in the patient with COVID-19: a randomised control trial (COPLA-II trial)

ImportanceNo proven treatment is available for severely ill COVID-19. Therapeutic use of COVID-19 convalescent plasma (COPLA) is under investigation.ObjectiveTo compare the efficacy of COPLA with standard medical therapy (SMT) alone...

Effects of synbiotic supplementation on serum adiponectin and inflammation status of overweight and obese breast cancer survivors: a randomized, triple-blind, placebo-controlled trial.

Adipokines and inflammatory factors can affect breast cancer (BC) prognosis and recurrence among breast cancer survivors (BCSs). This study was to evaluate the effects of synbiotic supplementation along with a low-calorie diet on some recurrence-related factors such as adiponectin, tumor necrosis factor-alpha (TNF-α), and high-sensitivity C-reactive protein (hs-CRP) among obese and overweight BCSs. We performed a randomized, triple-blind, placebo-controlled clinical trial among 76 overweight or obese postmenopausal women with a history of hormone-receptor-positive BC. Participants were randomly divided into 2 groups to intake either 109 CFU/day synbiotic supplement or placebo (n = 38 each group) for 8 weeks. All participants were given a low-calorie diet program. The primary outcome was serum concentration of adiponectin which was measured at baseline and after 8 weeks. Compared with the placebo, synbiotic intake significantly increased adiponectin (+ 13.58 (10.08, 18.17) vs. - 0.42 (- 2.90, 1.98) μg/ml; P < 0.001). In addition, synbiotic supplementation resulted in significant reduction in TNF-α levels (- 17.09 (- 32.05, - 13.60) vs. 0.20 (- 3.97, 2.00) ng/L; P < 0.001) and hs-CRP levels (- 1.14 (- 1.90, - 0.88 vs. - 0.06 (- 0.38, 0.15) mg/L; P < 0.001) compared with the placebo. In conclusion, 8-week synbiotic consumption by overweight and obese postmenopausal BCSs had beneficial effects on adiponectin, TNF-α, and hs-CRP. IRCT, IRCT20091114002709N49. Registered 18 May 2018, http://www.irct.ir : IRCT20091114002709N49.

Response of proinflammatory cytokine, tumor necrosis factor-alpha to moderate physical activity in nondiabetic hypertensives and type 2 diabetic hypertensives

Introduction: Hypertension is a multifactorial disease and is a major risk factor for cardiovascular disease, particularly in patients of diabetes mellitus. Management of hypertension is one of the critical components of comprehensive clinical management of diabetics. Aim: The aim of this study is to evaluate the effect of physical activity on systemic inflammation in patients with hypertension and type 2 diabetes mellitus in patients with hypertension. Methods: A total of 100 participants of either gender aged 40–69 years of Stage 2 essential hypertension were included in the study and assigned to 12 weeks of moderate physical activity (walking 10,000 steps/day). These study participants were further divided into two groups: type 2 diabetic (n =66) and nondiabetic (n = 34) hypertensives. Anthropometric parameters were noted and biochemical variables estimated at baseline and postintervention and evaluated statistically. Results: Twelve weeks of walking resulted in improved levels of inflammatory cytokine tumor necrosis factor-alpha (TNF-α). Systolic and diastolic blood pressure (BP) were reduced from 168.98 ± 3.76 to 154.29 ± 7.48 mmHg and from 103.38 ± 2.46 to 89.08 ± 3.62 mmHg, respectively. Body weight and body mass index were reduced from 69.8 ± 7.09 to 68.3 ± 6.53 kg and 23.21 ± 3.35 to 22.70 ± 3.16 kg/m2, respectively. A significant decrease in glycated hemoglobin (Group 1: 8.36% ± 1.83% vs. 7.74% ± 1.82%; Group 2: 5.56% ± 0.4% vs. 5.09% ± 0.19%) was found. A significant reduction in TNF-α levels in hypertensives with diabetes and a significant (P

Andrographolide does not protect against neuroinflammation in a Parkinsonism model: Focus on tumor necrosis factor alpha

The incidence of Parkinson's disease has increased in recent years, with pathological theories newly emerging. One of the most acknowledged theories is the neuroinflammation theory, which involves microglial activation and the expression of proinflammatory cytokines. Previous studies have confirmed the effects of andrographolide on anti-inflammatory characteristics; however, the role of andrographolide as a neuroprotective agent in 1-methyl-4-phenyl-1,2,3,4-tetrahydropiridine (MPTP)-induced Parkinsonism remains unknown. In this study, we used several doses of andrographolide and investigated its potential as a neuroprotective agent in an MPTP-induced Parkinsonism model. Five types of treatment were used for five groups of C57BL/6 mice. These treatments included (1) normal control, (2) MPTP treated, (3) MPTP and selegiline treated, (4) andrographolide treated at 5 mg/kgbw, and (5) andrographolide treated at 50 mg/kgbw. Immunohistochemical analyses were performed to determine tumor necrosis factor-alpha (TNFα) levels. No significant differences were observed in TNFα levels between control groups and those treated with andrographolide. TNFα levels were determined to be 10.0 ± 3.5 for the normal group, 8.4 ± 2.9 for the selegiline-treated group, 12.8 ± 7.8 for the MPTP-treated group, 5.4 ± 2.4 for the andrographolide-treated group at 50 mg/kgbw, and 5.8 ± 1.6 for the andrographolide-treated group at 5 mg/kgbw. This study suggests that no significant reduction of TNFα levels occur after treatment with andrographolide at doses of 5 and 50 mg/kgbw in an MPTP-treated Parkinsonism model, indicating no neuroprotective effect of andrographolide.

Evaluation of Level of TNF-α in Chronic Periodontitis Patients with Gestational Diabetes Mellitus after Phase I Periodontal Therapy

Background: There is little number of studies that address the inter-relationship of gestational diabetes mellitus (GDM) and periodontitis during pregnancy. Hence, this study was conducted to provide further evidence in the possible association between chronic periodontitis and GDM by evaluating the level of Tumor necrosis factor-alpha (TNF-α) of chronic periodontitis patients with GDM after phase I periodontal therapy.Subjects and methods: This study was conducted on 40 subjects divided into 2 groups: 20 pregnant females suffering from gestational diabetes mellitus associated with moderate to severe chronic periodontitis and 20 systemically free pregnant females suffering from moderate to severe chronic periodontitis. The periodontal status of the subjects was assessed at baseline before phase I periodontal therapy and 2 months after completion of the treatment: All subjects have been screened by comprehensive periodontal examination and full periodontal charts were obtained. The following clinical parameters were assessed to determine the clinical periodontal status of patients: Plaque Index (PI), Gingival Index (GI), Probing Pocket Depth (PPD), and Clinical Attachment Level (CAL). Gingival crevicular fluid (GCF) and serum samples were collected from both study groups to detect TNF-α levels. Regarding the assessment of TNF-α, Real-time reverse-transcriptase Polymerase Chain Reaction (RT) PCR technique was used.Results: Results of the present study observed statistically significant reduction in TNF-α levels after 2 months from phase I periodontal therapy. The current study showed that, there was a statistically significant positive (direct) correlation between TNF-α level, PI, GI, PPD and CAL measurement at baseline and after 2 months from phase I periodontal therapy.Conclusion: It is shown that the levels of TNF-α in GCF and serum before treatment were higher in GDM group (group 1) than in the control group. Thus, the examination of TNF-α may enhance the understanding of pathogenesis of periodontitis and GDM and its assessment in the treatment process may result in better control of the disease.

Low-dose celecoxib improves coronary function after acute myocardial ischaemia in rabbits

The role of celecoxib in cardiovascular events remains contentious. The aim of the present study was to investigate the effects of celecoxib in acute myocardial ischaemia (AMI) in rabbits in comparison with those of another non-steroidal anti-inflammatory drug, namely aspirin. Male New Zealand white rabbits were divided into four groups: (i) a sham-operated group; (ii) an AMI group, in which the left anterior descending coronary arteries were occluded for 60min; (iii) the celecoxib+AMI group, pretreated with 3mg/kg celecoxib, twice a day, for 3days before AMI induction; and (iv) the aspirin+AMI group, pretreated with 12.5mg/kg aspirin, twice a day, for 3days before AMI induction. Haemodynamic parameters were monitored using a multichannel physiological recorder. Serum levels of creatine kinase (CK), malondialdehyde (MDA), cyclo-oxygenase-2 (COX-2), tumour necrosis factor (TNF)-α, total nitrate/nitrite (NO(x) ), nitric oxide synthase (NOS) and myocardial infarct size were determined. Changes in isometric tension of isolated coronary rings were recorded by a myograph system. Compared with the sham group, the AMI group had lower blood pressure, higher left ventricular (LV) end-diastolic pressure, depressed maximum dP/dt of LV pressure, a larger infarct size and higher CK and MDA levels. Celecoxib, but not aspirin, pretreatment significantly ameliorated these effects of AMI. Celecoxib reversed AMI-induced increases in COX-2 levels to a similar extent as aspirin. Pretreatment with celecoxib resulted in a significant reduction in TNF-α levels and an increase in NO(x) and NOS levels compared with the AMI group. The dysfunctional vasoconstriction and vasodilation of coronary arteries were ameliorated by celecoxib administration. 4. In conclusion, the experimental evidence suggests that celecoxib exerts its protective effects in a COX-independent manner.

Estradiol and thermoregulation in adult endotoxemic rats exposed to lipopolysaccharide in neonatal life

Early life immune challenge has been considered an adaptive defense strategy against potential pathogens when the innate immune system is not completely developed. This study assesses whether neonatal endotoxin challenge alters body temperature response in adult female rats during endotoxemic shock and also, whether ovarian hormones may participate in this response. Rats were intraperitoneally injected with lipopolysacharide (LPS) or saline at post-natal day 14, then as adults they were submitted to endotoxemic shock. The LPS injection in adult neonatal Saline rats caused an initial hypothermia, followed by a febrile response. However, neonatal LPS showed an increased hypothermic response and an attenuation of fever. The bilateral ovariectomy abolished the difference in body temperature between the neonatal LPS and saline rats. To determine the dependence of ovarian hormones, ovariectomized rats treated with estradiol cypionate (ECP) restored hypothermia and the suppressed febrile response. However, the same results were not obtained when the animals were supplemented with ECP and medroxyprogesterone acetate (MPA). The neonatal LPS rats displayed a significant reduction in TNF-α levels and an increase in IL-10 levels when compared with saline animals. The ECP injection significantly enhanced IL-10 and suppressed TNF-α in neonatal LPS, but it did not change the inflammatory response in the saline rats. The ECP + MPA regiment in the neonatal LPS rats reduced TNF-α, but eliminated IL-10 stimulation in comparison with the saline group. The present investigation shows that neonatal LPS challenge alters the thermoregulatory response during endotoxemic shock in adulthood and the mechanism for this difference could be mediated by sex hormones, especially estradiol.

Butylated hydroxytoluene and N-acetylcysteine attenuates tumor necrosis factor-alpha (TNF-alpha) secretion and TNF-alpha mRNA expression in alveolar macrophages from human lung transplant recipients in vitro.

Tumor necrosis factor-alpha (TNF-alpha) is a polypeptide cytokine principally produced by macrophages/monocytes and commonly associated with inflammatory conditions. The present study was designed to investigate whether the antioxidants butylated hydroxytoluene (BHT) and N-acetylcysteine (NAC) modified TNF-alpha production in stimulated and unstimulated alveolar macrophages from lung transplant recipients in vitro. The effects of BHT and NAC on TNF-alpha production were studied both with and without lipopolysaccharide (LPS) activation of alveolar macrophages from bronchoalveolar lavage fluid. TNF-alpha was quantitated in cell culture medium using an enzyme-linked immunosorbent assay. TNF-alpha mRNA expression was analyzed by quantitative reverse transcription-polymerase chain reaction on total RNA extracted from the incubated alveolar macrophages. In unstimulated alveolar macrophages, TNF-alpha levels were significantly reduced by incubation with BHT or NAC. When alveolar macrophages from patients with cytomegalovirus infection were incubated with BHT, TNF-alpha secretion was significantly lowered. A significant reduction of TNF-alpha levels in LPS-stimulated alveolar macrophages was obtained in the presence of BHT or NAC. Our data from quantitative reverse transcription-polymerase chain reaction showed that the observed decrease in protein levels of TNF-alpha was associated with a decrease in TNF-alpha mRNA expression. Our results indicate that antioxidant treatment may be an effective step to lower the inflammatory process caused by cytomegalovirus infection or in endotoxin (LPS)-activated macrophages. The therapeutic use of antioxidant compounds could, therefore, be of interest in conditions such as lung transplantation, in which oxidative stress and inflammation can contribute significantly to the loss of allograft function.