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1.
TNFα stimulates NO release in EA.hy926 cells by activating the CaMKKβ-AMPK-eNOS pathway.
Dymkowska, D, Drabarek, B, Michalik, A, Nowak, N, Zabłocki, K
The international journal of biochemistry & cell biology. 2019;:57-67
Abstract
Previously we showed that a mild stimulation of EA.hy926 cells with tumour necrosis factor alpha (TNFα) activated mitochondrial biogenesis, probably as a mechanism preventing cell death. This was accompanied by an increased phosphorylation of eNOS and elevation of NO release. The aim of the present study was to explain the biochemical basis of this effect. Our results indicate that eNOS is the only enzyme catalysing NO generation in EA.hy926 cells, and TNFα stimulates its activity by activating AMP-activated protein kinase (AMPK). Inhibition of AMPK with Compound C prevents the TNFα-induced activatory phosphorylation of endothelial nitric oxide synthase (eNOS) at Ser1177 and reduces the NO release. AMPK is activated by phosphorylation catalysed by liver kinase B1 (LKB1) and calcium/calmodulin-dependent protein kinase kinase beta (CaMKKβ), which are phosphorylated and thereby activated in the presence of TNFα. Moreover, CaMKKβ catalyses an activatory phosphorylation of sirtuin 1, which could deacetylate and activate eNOS both directly and indirectly by an elevating the LKB1 activity. TNFα hardly increases the nuclear fraction of sirtuin 1, thus its major activity is probably attributed to the cytosolic pool. This is in line with the elevated activity of eNOS. We conclude that the increased AMPK-dependent phosphorylation of eNOS at least partially explains the stimulation of NO generation by TNFα in EA.hy926 cells.
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2.
Resveratrol decreases TNFα-induced ICAM-1 expression and release by Sirt-1-independent mechanism in intestinal myofibroblasts.
Domazetovic, V, Bonanomi, AG, Stio, M, Vincenzini, MT, Iantomasi, T
Experimental cell research. 2019;(2):111479
Abstract
Up-regulation of intercellular adhesion molecule-1 (ICAM-1) and its soluble form are involved in the chronic inflammation. For the first time, we demonstrated that resveratrol (RE), a natural polyphenol with antioxidant and anti-inflammatory properties, reduces the increase of expression and release of ICAM-1, due to TNFα-induced oxidative stress, in a myofibroblast cell line derived from human colonic (18Co cells). RE is scavenger of radical oxygen species (ROS) and modulates signaling pathways in which Sirt-1 and NF-κB are involved. Effectively, in TNFα-stimulated 18Co cells RE decreases ROS production and increases Sirt-1 expression and activity, but it reduces TNFα-induced ICAM-1 up-regulation by a Sirt-1-independent mechanism, as demonstrated by EX527 and Sirt-1 siRNA treatments. RE inhibits TNFα-induced activation of NF-κB by reducing both ROS and the degradation of IκB-α, an endogenous inhibitor of NF-κB, with consequent decrease of NF-κB nuclear translocation. This study also shows that NF-κB is not the only factor involved in the TNFα-induced ICAM-1 up-regulation and confirms our previous evidence according to which TNFα increases ICAM-1 levels by redox- and non-redox-regulated mechanisms. RE can represent good and useful support in therapies for intestinal inflammatory diseases in which TNFα plays a crucial role in the increase of adhesion molecule expression.
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3.
Anti-TNF combination therapy in inflammatory bowel disease: de novo or selective?
Macaluso, FS, Orlando, A
Minerva gastroenterologica e dietologica. 2019;(4):291-297
Abstract
Anti-TNFs still remain the backbone of advanced therapies in inflammatory bowel diseases, but their efficacy is not universal and tends to diminish over time. As a consequence, there is the need for optimization of these treatments, and the use of combination therapy - i.e. an anti-TNF plus an immunosuppressant - is one of the main strategies. The rationale for this approach lies in the evidence that the immunosuppressant reduces the formation of antibodies directed against the anti-TNF, thus avoiding the reduction or elimination of circulating drug levels, and in the combination of the therapeutic effect of two drugs. Nowadays, two different combination therapies should be distinguished. In the "de novo" combination therapy, the anti-TNF is used in combination with an immunosuppressant from the beginning of the treatment, in order to prevent the formation of anti-drug antibodies. In the "selective" combination therapy, the immunosuppressant is added at a later time in patients who experience a loss of response during anti-TNF monotherapy due to the development of anti-drug antibodies. The purpose of this review is to summarize the available evidence on both de novo and selective combination therapy. In addition, we will express our point of view on the choice between these two different treatment modalities.
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4.
Effects of macular xanthophyll supplementation on brain-derived neurotrophic factor, pro-inflammatory cytokines, and cognitive performance.
Stringham, NT, Holmes, PV, Stringham, JM
Physiology & behavior. 2019;:112650
Abstract
PURPOSE Oxidative and inflammatory processes play a major role in stress-induced neural atrophy. There is a wide body of literature linking oxidative and inflammatory stress with reductions in neurotrophic factors, stress resilience, and cognitive function. Based on their antioxidant and anti-inflammatory capacity, we investigated the effect of the dietary carotenoids lutein and zeaxanthin, along with the zeaxanthin isomer meso-zeaxanthin (collectively the "macular xanthophylls" [MXans]) on systemic brain-derived neurotrophic factor (BDNF) and anti-oxidant capacity (AOC), and the pro-inflammatory cytokines TNF-α, IL-6, and IL-1β. To investigate higher-order effects, we assessed cognitive performance. METHODS 59 young (18-25 yrs.), healthy subjects participated in a 6-month, double-blind, placebo-controlled trial to evaluate the effects of MXan supplementation on the aforementioned serum parameters and cognitive performance. Subjects were randomly assigned to one of three groups: placebo, 13 mg, or 27 mg/day total MXans; all measures were taken at baseline and 6 months. Blood was obtained via fasting blood draw, and MXan concentration in the retina (termed macular pigment optical density [MPOD]) was measured via customized heterochromatic flicker photometry. Serum BDNF and cytokines were assessed via ELISA. Serum antioxidant capacity (AOC) and serum MXan concentrations were quantified via colorimetric microplate assay, and high-performance liquid chromatography, respectively. Cognitive performance was measured via a computer-based assessment tool (CNS Vital Signs). RESULTS BDNF, MPOD, serum MXans, and AOC all increased significantly versus placebo in both treatment groups over the 6-month study period (p < .05 for all). IL-1β decreased significantly versus placebo in both treatment groups (p = .0036 and p = .006, respectively). For cognitive measures, scores for composite memory, verbal memory, sustained attention, psychomotor speed, and processing speed all improved significantly in treatment groups (p < .05 for all) and remained unchanged in the placebo group. Several measures were found to be significantly associated in terms of relational changes over the course of the study. Notably, change in BDNF was related to change in IL-1β (r = -0.47; p < .001) and MPOD (r = 0.44; p = .0086). Additionally, changes in serum MXans were strongly related to AOC (r = 0.79 & 0.61 for lutein and zeaxanthin isomers respectively; p < .001). For cognitive scores, change in BDNF was correlated to change in composite memory (r = 0.32; p = .014) and verbal memory (r = 0.35; p = .007), whereas change in MPOD was correlated with change in both psychomotor speed (r = 0.38; p = .003), and processing speed (r = 0.35; p = .007). Change in serum lutein was found to be significantly correlated to change in verbal memory (r = 0.41; p < .001), composite memory (r = 0.31; p = .009), and sustained attention (r = 0.28; p = .036). Change in serum zeaxanthin isomers was significantly correlated with change in verbal memory (r = 0.33; p = .017). Lastly, change in AOC was significantly associated with verbal memory (r = 0.34; p = .021), composite memory (r = 0.29; p = .03), and sustained attention (r = 0.35; p = .016). No significant relational changes in any cognitive parameter were found for the placebo group. CONCLUSIONS Six months of daily supplementation with at least 13 mg of MXans significantly reduces serum IL-1β, significantly increases serum MXans, BDNF, MPOD, and AOC, and improves several parameters of cognitive performance. Findings suggest that increased systemic antioxidant/anti-inflammatory capacity (and not necessarily deposition of the carotenoids in neural tissues), may explain many of the effects determined in this study. The significant relationship between change in BDNF and IL-1β over the course of the study suggests that regular consumption of MXans interrupts the inflammatory cascade that can lead to reduction of BDNF. Changes in MPOD and BDNF appear to account for enhancement in cognitive parameters that involve speed of processing and complex processing, respectively. ISRCTN Clinical Trial Registration: ISRCTN16156382.
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5.
Use of biosimilars in inflammatory bowel disease: a position update of the Italian Group for the Study of Inflammatory Bowel Disease (IG-IBD).
Fiorino, G, Caprioli, F, Daperno, M, Mocciaro, F, Principi, M, Viscido, A, Fantini, MC, Orlando, A, Papi, C, Annese, V, et al
Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver. 2019;(5):632-639
Abstract
The first infliximab biosimilar for the treatment of inflammatory bowel disease (IBD) was introduced in 2013, and today eight anti-TNF alpha biosimilars (three for infliximab and five for adalimumab) have been approved and licensed by the European Medicines Agency. Biosimilars present great potential in terms of cost saving and possible consequential reinvestment in the health care system. The increasing knowledge about the process of biosimilar development and use in IBD and the publication of many prospective clinical studies and real-life clinical experiences have progressively changed the point of view of IBD physicians. In the present position paper, the Italian Group for the Study of Inflammatory Bowel Disease present and discuss their updated statements and positions on this topic, with emphasis on the concepts of biosimilarity and extrapolation across indications, safety and immunogenicity, interchangeability and switching, automatic substitution, and, finally, patient education about biosimilars.
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6.
Even Short-Term Telmisartan Treatment Ameliorated Insulin Resistance But Had No Influence on Serum Adiponectin and Tumor Necrosis Factor-Alpha Levels in Hypertensive Patients with Metabolic Syndrome.
Kiyici, S, Guclu, M, Budak, F, Sigirli, D, Tuncel, E
Metabolic syndrome and related disorders. 2019;(3):167-172
Abstract
BACKGROUND We investigated the effect of short-term telmisartan usage in addition to lifestyle changes such as diet and exercise on insulin resistance, lipid metabolism, and serum adiponectin and tumor necrosis factor-alpha (TNF-α) levels in hypertensive patients with metabolic syndrome (MetS). METHODS A total of 36 hypertensive patients with MetS were randomized to telmisartan and control groups in an open-labeled prospective study. RESULTS There were significant decreases in anthropometric variables of patients according to baseline measurements in both groups at the end of the study. Serum insulin level and insulin resistance assessed by homeostasis model assessment-insulin resistance were decreased significantly in the telmisartan group (P = 0.040 and P = 0.034, respectively) compared with the controls, while there was no statistically significant change in the lipid profiles of the two groups. Serum adiponectin level was increased by 19.1% ± 41.7% in the telmisartan group, but intergroup analysis revealed no significant change. There was also no significant change in serum TNF-α level in either group. CONCLUSION It has been observed that even short-term telmisartan treatment had favorable effects on insulin resistance and glucose metabolism compared with lifestyle changes alone. The fundamental effect of telmisartan treatment on insulin resistance renders it a good therapeutic option for hypertensive patients with MetS.
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7.
Garlic Supplementation Reduces Circulating C-reactive Protein, Tumor Necrosis Factor, and Interleukin-6 in Adults: A Systematic Review and Meta-analysis of Randomized Controlled Trials.
Darooghegi Mofrad, M, Milajerdi, A, Koohdani, F, Surkan, PJ, Azadbakht, L
The Journal of nutrition. 2019;(4):605-618
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Abstract
BACKGROUND Conflicting findings on the effects of garlic supplementation on inflammatory biomarkers have been observed in randomized clinical trials (RCTs). OBJECTIVES The aim of this study was to summarize study results regarding the effects of garlic supplementation on serum inflammatory biomarkers in adults. METHODS We searched Scopus, PubMed, Google Scholar and Cochrane library databases for relevant papers published until April 2018, using keywords such as "garlic" and "inflammatory biomarker." We included RCTs that 1) were conducted in adults, 2) examined the effects of garlic supplementation on inflammatory biomarkers compared to a control group, and 3) reported sufficient data on inflammatory biomarkers. Results were reported as weighted mean differences (WMD) with 95% CI using random effects models. Cochrane's Q and I-squared (I2) tests were used to determine heterogeneity among studies. Funnel plots and Egger's regression test were used to assess publication bias. RESULTS Sixteen RCTs were included. Garlic doses ranged from 12 to 3600 mg/d, and intervention duration ranged from 2 to 52 wk. Garlic administration significantly reduced serum C-reactive protein (CRP) (n = 13) (WMD: -0.61 mg/L, 95% CI: -1.12, -0.11, P = 0.018, I2 = 76.9%), IL-6 (n = 5) (WMD: -0.73 ng/L, 95% CI: -1.06, -0.40, P < 0.001, I2 = 0%), and TNF (n = 7) (WMD: -0.26 ng/L, 95% CI: -0.41, -0.12, P < 0.001, I2 = 0.0%), compared to controls. However, the effect of garlic supplementation on serum adiponectin (n = 3) (WMD: 0.18 µg/L, 95% CI: -0.21, 0.57, P = 0.35, I2 = 60.7%) and leptin (n = 2) (WMD: -1.25 µg/L, 95% CI: -2.64, 0.14, P = 0.07, I2 = 0.0%) concentrations were not significant. CONCLUSION In this meta-analysis of RCTs, we found that garlic supplementation reduced serum concentrations of CRP, TNF, IL-6, but did not affect serum adiponectin and leptin in adults. More RCTs are needed to test the effects of garlic supplementation on inflammation.
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The Value of Total antioxidant Status and Serum Tumor Necrosis Factor-α Levels at 24-28 Weeks of Gestation in the Prediction of Optimal Treatment Protocol in Gestational Diabetes Mellitus.
Ozler, S, Oztas, E, Uygur, D, Ersoy, AO, Ergin, M, Koca, C, Danisman, N, Erkaya, S
Experimental and clinical endocrinology & diabetes : official journal, German Society of Endocrinology [and] German Diabetes Association. 2019;(7):485-491
Abstract
AIM: The aim of this study was to investigate the serum oxidative stress markers, antioxidant enzyme and tumor necrosis factor-α (TNF-α) levels at 24-28 weeks of gestation and to evaluate the predictive value of them on the subsequent treatment protocol in gestational diabetes mellitus (GDM). METHODS A total of 58 GDM patients (30 treated with only conventional healthy dietary recommendation (CHDR), 28 treated with insulin) and 30 healthy pregnant women at 24-28 weeks of gestation, were enrolled in this prospective case-control study. The oxidative status, antioxidant enzyme and TNF-α levels were evaluated to determine if there is an association with the need of insulin therapy for glycemic control by using multivariable logistic regression analysis. RESULTS TNF-α (OR=11.976, 95%CI: 2.441-58.754, P=0.002) and total antioxidant status (TAS) (OR=12.769, 95%CI: 2.464-66.182, P=0.002) were found to be predictive for GDM at 24-28 weeks of gestation. Besides, further evaluation considering the treatment modality showed that increased TNF-α (OR=18.615, 95%CI: 2.338-148.240, P=0.006) and lower TAS levels (OR=99.471, 95%CI: 2.865-3 453.061, P=0.011) were independent predictors of the need for insulin treatment in GDM patients. CONCLUSIONS Increased TNF-α levels and low TAS are significantly associated with the increased risk of insulin requirement for achieving good glycemic control in GDM.
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Clinical intervention using Bifidobacterium strains in celiac disease children reveals novel microbial modulators of TNF-α and short-chain fatty acids.
Primec, M, Klemenak, M, Di Gioia, D, Aloisio, I, Bozzi Cionci, N, Quagliariello, A, Gorenjak, M, Mičetić-Turk, D, Langerholc, T
Clinical nutrition (Edinburgh, Scotland). 2019;(3):1373-1381
Abstract
BACKGROUND & AIMS Celiac disease (CD) is an immune-mediated systemic disease, caused by ingestion of gluten in genetically predisposed individuals. Gut microbiota dysbiosis might play a significant role in pathogenesis of chronic enteropathies and its modulation can be used as an intervention strategy in CD as well. In this study, we aimed to identify correlations between fecal microbiota, serum tumor necrosis factor alpha (TNF-α) and fecal short-chain fatty acids (SCFAs) in healthy children and children with CD after administration of probiotic Bifidobacterium breve BR03 and B632. METHODS A double-blind placebo-controlled study enrolled 40 children with CD (CD) and 16 healthy children (HC). CD children were randomly allocated into two groups, of which 20 belonged to the placebo (PL) group and 20 to the Probiotic (PR) group. The PR group received a probiotic formulation containing a mixture of 2 strains, B. breve BR03 (DSM 16604) and B. breve B632 (DSM 24706) in 1:1 ratio for 3 months. Subsequently, for statistical analysis, blood and fecal samples from CD children (on enrolment - T0 and after 3 months, at the end of intervention with probiotic/placebo - T1) and HC children were used. The HC group was sampled only once (T0). RESULTS Verrucomicrobia, Parcubacteria and some yet unknown phyla of Bacteria and Archaea may be involved in the disease, indicated by a strong correlation to TNF-α. Likewise, Proteobacteria strongly correlated with fecal SCFAs concentration. The effect of probiotic administration has disclosed a negative correlation between Verrucomicrobia, some unknown phyla of Bacteria, Synergistetes, Euryarchaeota and some SCFAs, turning them into an important target in microbiome restoration process. Synergistetes and Euryarchaeota may have a role in the anti-inflammatory process in healthy human gut. CONCLUSIONS Our results highlight new phyla, which may have an important relation to disease-related parameters, CD itself and health.
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10.
Probiotics May Have Beneficial Effects in Parkinson's Disease: In vitro Evidence.
Magistrelli, L, Amoruso, A, Mogna, L, Graziano, T, Cantello, R, Pane, M, Comi, C
Frontiers in immunology. 2019;:969
Abstract
Background: Parkinson's disease (PD) is characterized by loss of dopaminergic neurons and intraneuronal accumulation of alpha-synuclein, both in the basal ganglia and in peripheral sites, such as the gut. Peripheral immune activation and reactive oxygen species (ROS) production are important pathogenetic features of PD. In this context, the present study focused on the assessment of in vitro effects of probiotic bacterial strains in PBMCs isolated from PD patients vs. healthy controls. Methods: 40 PD patients and 40 matched controls have been enrolled. Peripheral blood mononuclear cells (PBMCs) were isolated and co-cultured with a selection of probiotics microorganisms belonging to the lactobacillus and bifidobacterium genus. In vitro release of the major pro- (Tumor Necrosis Factor-alpha and Interleukin-17A and 6) and anti-inflammatory (Interleukin 4 and 10) cytokines by PBMCs, as well as the production of ROS was investigated. Furthermore, we assessed the ability of probiotics to influence membrane integrity, antagonize the growth of potential pathogen bacteria, such as Escherichia coli and Klebsiella pneumoniae and encode tyrosine decarboxylase genes (tdc). Results: All probiotic strains were able to inhibit inflammatory cytokines and ROS production in both patients and controls. The most striking results were obtained in PD subjects with L. salivarius LS01 and L. acidophilus which significantly reduced pro-inflammatory and increased the anti-inflammatory cytokines (p < 0.05). Furthermore, most strains determined restoration of membrane integrity and inhibition of E. coli and K. pneumoniae. Finally, we also showed that all the strains do not carry tdc gene, which is known to decrease levodopa bioavailability in PD patients under treatment. Conclusions: Probiotics exert promising in vitro results in decreasing pro-inflammatory cytokines, oxidative stress and potentially pathogenic bacterial overgrowth. In vivo longitudinal data are mandatory to support the use of bacteriotherapy in PD.