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To investigate the protective role of high dose melatonin concerning myocardial I/R injury and inflammation in patients undergoing on-pump coronary artery bypass grafting (CABG) surgery by evaluating IR/inflammatory biomarkers and clinical outcomes. This was a prospective; randomized; single-blinded placebo-controlled study conducted at cardio-thoracic surgery department of the Academy of the Cardiovascular and Thoracic Surgery, Ain Shams University. Eligible patients were randomly allocated to; melatonin-treated group (MTG) or placebo-treated group (PTG). The MTG ( n  = 17) received 60 mg/day melatonin capsules daily starting 5 days before surgery in addition to the standard of care. PTG ( n  = 17) received placebo also 5 days before surgery plus standard of care. The levels of nuclear factor kappa beta (NF-κb) (primary outcome), tumor necrosis factor (TNF-α), cardiac troponins I, and IL-6 levels were all assessed for both groups at five time points: baseline before melatonin or placebo administration (T0), before cross-clamp application(T1), 5 min after cross-clamp removal(T2), 6 h after cross-clamp removal(T3) and 24 h after cross-clamp removal(T4). Blood pressure was assessed at baseline, pre-operative and 24-hours post-operative. The Quality of recovery-40 score (QOR-40) was assessed for both groups on day 4 after surgery. TNF-α levels decreased in the MTG at T1( p  = 0.034) versus PTG. At T2( p  = 0.005), and T3( p  = 0.04), TNF-α significantly increased in PTG versus MTG. Troponins significantly increased in PTG at T3 ( p  = 0.04) versus MTG. NF-κB levels declined at T1 ( p  = 0.013) and T2 ( p  = 0.0001) in MTG compared to PTG. IL-6 significantly increased in PTG versus MTG at T3 ( p  = 0.04). The QOR-40 score significantly decreased in MTG versus PTG. MTG had statistically significant decrease in DBP compared to the placebo group ( p  = 0.024). MTG had a statistically significant shorter intubation time than did the placebo group ( p  = 0.03). Melatonin 60 mg was well-tolerated without any reported side effects. Our findings suggested that melatonin could ameliorate myocardial I/R injury after on-pump CABG and that this outcome was essentially correlated to its antiapoptotic and anti-inflammatory effects. Trial registration: ClinicalTrials.gov registration number NCT05552586, 9/2022.

Background and objectives NF-kB, SIRT1 and systemic inflammation factors including hs-CRP, IL-6 and TNF-α accelerate atherosclerosis pathogenesis. Our purpose was to evaluate the effect of daily supplementation of three-gram cinnamon on plasma levels of NF-kB, SIRT, hs-CRP, IL-6 and TNF-α among type 2 diabetes patients. Subjects and methods A randomized, double blind, and controlled clinical trial was performed with 44 adult patients who were 25 to 70 years old with type 2 diabetes, randomized to two intervention ( n  = 22) and control ( n  = 22) groups differing by daily three grams cinnamon supplementation and placebo for 8 weeks, respectively. The plasma levels of NF-kB, SIRT, hs-CRP, IL-6 and TNF-α were measured by ELISA assay at the beginning and end of the study. Results After 8-week intervention, 39 subjects ( n  = 20 in the cinnamon and n  = 19 in the placebo groups) ended up the trial. It was not observed significant difference in levels of hs-CRP ( P  = 0.29), TNF-α ( P  = 0.27), IL-6 ( P  = 0.52), and Sirtuin-1 ( P  = 0.51) in between group comparison. While, the result showed significant difference in levels of NF-kB ( P  = 0.02) between groups. As well as, in among group comparison, there was not observed significant differences except in hs-CRP ( P  = 0.008) in placebo group. Conclusions This study elucidated that cinnamon supplementation has no beneficial effects in reduction of NF-kB, SIRT1, hs-CRP, IL-6 and TNF-α levels in type 2 diabetes patients which have a considerable role in development of atherogenesis.

Background Analyse the effects of Bifidobacterium BB-12 on intestinal metabolites and serum inflammatory factors in premature infants. Methods 71 premature infants at gestational age of ≤32 weeks were randomly divided into the probiotic ( n  = 36) and control ( n  = 35) groups. Faecal and blood samples were collected from the two groups of premature infants at the 2nd and 4th week of life for intestinal metabolite detection and assessment of the level of the serum inflammatory markers TLR4, NF- κ B, IL-1β, and TNF- α. Results Compared to the control group, the probiotic group contained more amino acids, these elements were enriched on multiple amino acid metabolic pathways, and the probiotic group showed significantly lower levels of the serum inflammatory markers TLR4, NF-κB, IL-1β, and TNF-α. Finally, the probiotic group showed a lower incidence of feeding intolerance. Conclusions The administration of Bifidobacterium BB-12 is associated with increasing the levels of glutamine, glutamic acid, and kynurenine in the gut of premature infants, and associated with reducing the levels of TLR4 and NF-κB in the serum, further decreasing the secretion of the pro-inflammatory factors IL-1β and TNF-α, and alleviating systemic inflammatory reactions, thereby reducing the incidence of feeding intolerance. Impact The use of Bifidobacterium BB-12 in premature infants can increase the levels of amino acids in the intestine. Increases in Bifidobacterium BB-12 may decrease the serum levels of TLR4, NF-κB, IL-1β, and TNF-α. Kynurenine may improve the prognosis of preterm infants by reducing inflammation. Bifidobacterium BB-12 may improve the feeding tolerance of premature infants, thus reducing the incidence of feeding intolerance.

Inflammation plays a significant role in the pathophysiology of depression. However, not all individuals exposed to inflammatory challenge develop depression, and identifying those at risk is necessary to develop targeted monitoring, prevention, and treatment strategies. Within a randomized double-blind placebo-controlled study (n = 115), we examined whether leukocyte transcriptome profiles predicted inflammation-induced depressed mood in volunteers who received low-dose intravenous endotoxin (n = 58; aged 18–50). At baseline, transcription factor (TF) activities were assessed using genome-wide transcriptional profiling of peripheral blood mononuclear cells and promoter-based bioinformatic analyses. Then, participants were administered endotoxin. Self-reported depressed mood was assessed using the Profile of Mood States. Based on extant studies linking transcriptional profiles to depressive disorder, we examined whether post-endotoxin depressed mood is predicted by baseline activity of TFs related to immune activation, sympathetic activation, and glucocorticoid insensitivity: respectively, nuclear factor kappa B (NF-kB), cAMP response element-binding protein (CREB), and glucocorticoid receptor (GR). Twenty-one participants (36%) experienced an increase in depressed mood from baseline to 2 h post endotoxin, when depressive response peaks. Bioinformatics analyses controlling for age, sex, ethnicity, body mass index, and physical sickness response revealed that post-endotoxin depressed mood was predicted by increased baseline activity of TFs related to inflammation (NF-kB) and beta-adrenergic signaling (CREB) and by decreased activity of GR-related TFs (P’s < 0.001). Inflammation-induced depressed mood is predicted by peripheral transcriptome profiles related to immune activation, sympathetic activation, and glucocorticoid insensitivity. With further replication, these stress-related molecular profiles could be used for a novel genomic approach for identifying individuals at high-risk for the inflammatory subtype of depression.

Activation of the innate immune system is thought to contribute to depression. Multiple social and behavioral factors are also known to instigate depression. Whether these socio-behavioral factors interact with inflammatory stimuli to alter proinflammatory responses and depressed mood is not known. In 115 healthy adults, social, emotional, and behavioral factors were assessed at baseline. A single infusion of endotoxin (Escherichia coli; 0.8 ng/kg of body weight) or placebo (0.9% saline) was administered with hourly assessment of depressed mood and proinflammatory cytokines (interleukin-6 (IL-6); tumor necrosis factor-α (TNF)). Inflammatory gene expression was examined at 30 min after infusion, prior to increase of inflammatory cytokines. As compared to placebo, endotoxin-induced increases of depressed mood were moderated by baseline levels of perceived stress, trait sensitivity to social disconnection, and severity of symptoms of anxiety and depression (all Ps < 0.05) but not early life stress, social status, social support, neuroticism, or sleep disturbance. Anxiety symptoms remained significant in multivariable analyses (P < 0.01). None of these socio-behavioral factors were related to increases in proinflammatory cytokines. Transcriptome profiling analyses indicated that perceived stress, sensitivity to social disconnection, and depressive symptoms were associated with increased activation of pro-inflammatory transcription control pathways (i.e., activator protein-1, nuclear factor-κB) in response to endotoxin (all Ps < 0.05). These results indicate that an array of socio-behavioral factors, which are associated with depression risk, modify vulnerability to inflammation-induced depressed mood. Together, these observations may be used to help target therapeutic interventions to mitigate occurrence of the inflammatory biotype of depression.

Abstract Rationale Simvastatin inhibits inflammatory responses in vitro and in murine models of lung inflammation in vivo. As simvastatin modulates a number of the underlying processes described in acute lung injury (ALI), it may be a potential therapeutic option. Objectives To investigate in vivo if simvastatin modulates mechanisms important in the development of ALI in a model of acute lung inflammation induced by inhalation of lipopolysaccharide (LPS) in healthy human volunteers. Methods Thirty healthy subjects were enrolled in a double-blind, placebo-controlled study. Subjects were randomized to receive 40 mg or 80 mg of simvastatin or placebo (n = 10/group) for 4 days before inhalation of 50 μg LPS. Measurements were performed in bronchoalveolar lavage fluid (BALF) obtained at 6 hours and plasma obtained at 24 hours after LPS challenge. Nuclear translocation of nuclear factor-κB (NF-κB) was measured in monocyte-derived macrophages. Measurements and Main Results Pretreatment with simvastatin reduced LPS-induced BALF neutrophilia, myeloperoxidase, tumor necrosis factor-α, matrix metalloproteinases 7, 8, and 9, and C-reactive protein (CRP) as well as plasma CRP (all P < 0.05 vs. placebo). There was no significant difference between simvastatin 40 mg and 80 mg. BALF from subjects post-LPS inhalation induced a threefold up-regulation in nuclear NF-κB in monocyte-derived macrophages (P < 0.001); pretreatment with simvastatin reduced this by 35% (P < 0.001). Conclusions Simvastatin has antiinflammatory effects in the pulmonary and systemic compartment in humans exposed to inhaled LPS. Clinical trial registered with www.controlled-trials.com (ISRCTN21056528).

Objective This study aims to assess the safety as well as effectiveness of Cilostazol as a complementary therapy to methotrexate among individuals with active rheumatoid arthritis. Method This study was a randomly allocated, double-blind, placebo-controlled parallel design involving 70 patients who were diagnosed with active rheumatoid arthritis. Participants were randomly assigned to two sets: the control group ( n  = 35) which received methotrexate \"MTX\" (7.5 mg IM weekly) plus placebo tablets twice daily and the Cilostazol group ( n  = 35), which received the same MTX\" dose plus Cilostazol 50 mg twice daily for 3 months. Patients were assessed to determine the serum levels of C-reactive protein (CRP) nuclear factor kappa B (NF-κB), hemoxygenase-1 (HO-1), and cyclic adenosine monophosphate (cAMP). Disease Activity Score (DAS28-CRP), Multidimensional Health Assessment Score (MDHAQ), and morning stiffness duration were also assessed. Results The Cilostazol group produced a significant improvement in cAMP level as compared to the control group ( P  = 0.001) . cAMP level showed a significant inverse correlation with DAS28-CRP ( r  = −0.336; P  = 0.004). However, Cilostazol group produced non-significant improvements in the serum levels of the other biological markers (CRP, NF-κB, and HO-1), DAS28-CRP score, MDHAQ score, and morning stiffness duration as compared to the control group (P > 0.05). The implication of Cilostazol for patients with rheumatoid arthritis was tolerable and safe. Conclusion The beneficial effect of Cilostazol on cAMP and the negative correlation between cAMP and DAS28-CRP could support its impact on the disease activity. Further research seems necessary to elucidate the mechanisms underlying the link between cAMP and disease activity. Trial registration Clinical Trials.gov identifier: NCT05594680 , The date of registration is: 30/10/2022.

IntroductionCurcumin reduces gut barrier damage and plasma cytokine responses to exertional heat stress. However, the role of peripheral blood mononuclear cell (PBMC) in this response remains unclear.PurposeThis work investigated the effect of 3 days of 500 mg/day dietary curcumin supplementation on PBMC responses to exertional heat stress in non-heat acclimated humans.MethodsEight participants ran (65% VO2max) for 60 min in an environmental chamber (37 °C/25% RH) two times (curcumin/placebo). Blood samples were collected pre, post, 1 h post, and 4 h post-exercise. PBMC were isolated from blood samples and the protein content of markers along the TLR4 signaling pathway (TLR4, MyD88, pNF-κB, NF-κB), indicators of cellular energy status (SIRT1 and p-AMPK), and mediators of cellular heat shock response (pHSF-1 and HSP70) were examined with Western blot. Data were analyzed with two-way (condition × time) RM-ANOVAs with Newman–Keuls post hocs.ResultsAs compared to placebo, curcumin did not alter protein expression in PBMC (p > 0.05). However, in both study conditions at 1 h post-reductions were noted in TLR 4 (− 21.5%; p = 0.03), HSP70 (− 11.0%; p = 0.04), pAMPK (− 48.5%; p < 0.01), and SIRT1 (− 47.8%; p < 0.01). Remarkably, the ratio of pNF-κB to NF-κB was elevated in both conditions at this same timepoint (+ 75.4%; p = 0.02).ConclusionsInflammatory protein expression in PBMC did not differ between curcumin and placebo conditions. Downregulation of pAMPK/SIRT1 and release of HSP70 to the bloodstream may compensate for reduced TLR4, allowing PBMC to maintain inflammatory capacity and preventing an “open window” during the hours following hyperthermic exercise.

High-fat, high-carbohydrate (HFHC) meals induce an inflammatory response in mononuclear cells (MNC). Here, we studied the interaction between metabolic and inflammatory signalling pathways by the measurement of postprandial effects of three different test meals on intracellular Akt, S6 kinase (S6K)/mammalian target of rapamycin and NF-κB signalling in human MNC. We recruited six healthy, lean individuals. Each individual ingested three different meals in the morning separated by at least 3 d: a HFHC meal; an oral lipid-tolerance test meal; a healthy breakfast. Blood samples were obtained before and 1, 2, 4, 6 and 8 h after ingestion. Plasma insulin and IL-6 levels were measured. Intracellular metabolic and inflammatory signalling pathways were assessed by measuring the phosphorylation of Akt kinase and S6K, the degradation of inhibitory κB-α (IκB-α) protein and the DNA binding activity of NF-κB in MNC. mRNA expression levels of the Akt and NF-κB target genes Mn superoxide dismutase (MnSOD), CC-chemokine-receptor 5 (CCR5), intercellular adhesion molecule 1 (ICAM-1) and plasminogen activator inhibitor-1 (PAI-1) were measured by quantitative RT-PCR. We found a positive correlation of Akt phosphorylation with NF-κB activation (NF-κB binding activity: r 0·4500, P= 0·0003; IκB-α protein levels: r − 0·5435, P< 0·0001), a negative correlation of plasma insulin levels with NF-κB binding activity (r − 0·3993, P= 0·0016) and a positive correlation of plasma insulin levels with S6K activation (r 0·4786, P< 0·0001). The activation of Akt and pro-inflammatory NF-κB signalling was supported by the up-regulation of the respective target genes MnSOD and CCR5. In conclusion, the present data suggest a postprandial interaction between the metabolic and inflammatory signalling pathways Akt and NF-κB in MNC.

During aging, chronic systemic inflammation increases in prevalence and antioxidant balance shifts in favor of oxidant generation. Avenanthramide (AVA) is a group of oat phenolics that have shown anti-inflammatory and antioxidant capability. The present study investigated whether dietary supplementation of avenanthramides (AVA) in oats would increase antioxidant protection and reduce inflammation after a bout of downhill walking (DW) in postmenopausal women. Women at age of 50–80 years (N = 16) were randomly divided into two groups in a double-blinded fashion, receiving two cookies made of oat flour providing 9.2 mg AVA or 0.4 mg AVA (control, C) each day for 8 weeks. Before and after the dietary regimen, each group of subjects walked downhill on a treadmill (−9% grade) for 4 bouts of 15 minutes at a speed of 4.0 km/h with 5 minutes rest between sessions. Blood samples were collected at rest, 24 h post-DW, and 48 h post-DW pre- and post-supplementation. Both DW sessions increased plasma creatine kinase activity (P < 0.05). Before supplementation, in vitro neutrophil respiratory burst (NRB) activity was increased at 24 h post-DW (P < 0.05) and C-reactive protein (CRP) was increased 48 h post-DW (P < 0.05). AVA supplementation decreased DW-induced NRB at 24 h (P < 0.05) and CRP level 48 h (P < 0.05). Plasma interleukin (IL)-1β concentration and mononuclear cell nuclear factor (NF) κB binding were suppressed at rest and during post-DW period in AVA but not C group (P < 0.05). Plasma total antioxidant capacity (P < 0.05) and erythrocyte superoxide dismutase activity were increased in AVA vs. C (P < 0.05), whereas glutathione redox status was elevated 48 h post-DW but not affected by AVA. Thus, chronic AVA supplementation decreased systemic and DW-induced inflammation and increased blood-borne antioxidant defense in postmenopausal women.