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Background and Aims: The clinical, prognostic, and therapeutic impact of adrenal insufficiency in acute liver failure (ALF) and acute-on-chronic liver failure (ACLF) remains controversial and exact diagnostic criteria are lacking. We sought to determine the diagnostic and therapeutic value of cortisol measurement and glucocorticoid (GC) treatment in ALF and ACLF. Methods: 28-day transplant-free survival (TFS) was studied in relation to absolute cortisol concentrations and to GC treatment in ALF (n = 30) and ACLF (n = 34) patients. Cortisol concentrations and short synacthen test were assessed by chemiluminescence immunoassay and liquid chromatography-mass spectrometry. Clinicians decided independently on GC treatment. In relation, phenotypic and functional characteristics of circulating monocytes were assessed. Results: In ALF, baseline cortisol concentrations <387 nmol/L predicted TFS (sensitivity 83%, specificity 53%). In ACLF, baseline cortisol <392 nmol/L correlated with TFS (sensitivity 80%, specificity 61%). In both, ALF and ACLF, GC treatment did not influence 28-day TFS in patients with low baseline cortisol. However, in patients with baseline cortisol exceeding 387 and 392 nmol/L, respectively, TFS was higher if they had been treated with GC. High baseline cortisol was associated with low HLA-DR expression on monocytes. Conclusion: Our data suggest a prognostic value of baseline cortisol measurement in ALF and ACLF. Overall, strong activation of the hypothalamic-pituitary-adrenal axis indicated poor prognosis. Furthermore, baseline cortisol deserves prospective evaluation as a guide for GC treatment decision-making.
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BACKGROUND/AIMS: We previously demonstrated that anthocyanin-rich bilberry extract (ARBE) inhibits IFN-γ-induced signalling and downstream effects in human monocytic cells and ameliorates disease activity in ulcerative colitis (UC) patients. Here, we studied the molecular mechanisms of ARBE-mediated effects in vitro and by analysing colonic tissue and serum samples of UC patients treated with an oral anthocyanin-rich bilberry preparation during an open label clinical trial. METHODS: Colon specimens obtained during an open pilot study using ARBE for the treatment of mild-to-moderate UC were analyzed by immunohistochemistry. Cytokine levels in patients' serum were quantified by ELISA. Cell culture experiments were performed using THP-1 monocytic cells. RESULTS: ARBE treatment inhibited the expression of IFN-γ-receptor 2 in human THP-1 monocytic cells. Colon biopsies of UC patients who responded to the 6-week long ARBE treatment revealed reduced amounts of the pro-inflammatory cytokines IFN-γ and TNF-α. Levels of phosphorylated (activated) p65-NF-κB were reduced in these patients. Further, patients with successful ARBE treatment featured enhanced levels of Th17-cell specific cytokine IL-22 and immunoregulatory cytokine IL-10 as well as reduced serum levels of TNF-α and MCP-1, but enhanced levels of IL-17A, in contrast to patients that did not reach remission after ARBE treatment. CONCLUSIONS: Our data suggest a molecular mechanism underlying the anti-inflammatory effects of ARBE treatment in UC patients by modulating T-cell cytokine signalling and inhibiting IFN-γ signal transduction. These data are of particular interest, since ARBE is a promising therapeutic approach for the treatment of IBD.
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Antocianinas/farmacología , Colitis Ulcerosa/metabolismo , Citocinas/metabolismo , Vaccinium myrtillus/química , Adulto , Colitis Ulcerosa/patología , Femenino , Humanos , MasculinoRESUMEN
BACKGROUND/AIMS: Anthocyanins are plant-derived dietary components that are highly abundant, for example, in bilberries. We have previously demonstrated that anthocyanins exert anti-inflammatory properties in mouse colitis models and ameliorate disease activity in ulcerative colitis patients. Here, we studied the molecular mechanisms through which anthocyanin-containing bilberry extract (BE) exerts anti-inflammatory effects in human monocytic THP-1 cells. METHODS: THP-1 cells were pre-incubated with BE 20 min prior to TNF-α or IFN-γ (100 ng/ml each) stimulation. Signalling protein activation was studied by Western blotting, mRNA expression by quantitative PCR and cytokine secretion by ELISA. RESULTS: IFN-γ-induced phosphorylation of STAT1 and STAT3 was significantly reduced by BE co-treatment. Consequently, levels of mRNA expression and/or cytokine secretion of MCP-1, IL-6, TNF-α, ICAM-1, and T-bet were lower with BE co-treatment. In contrast, BE enhanced TNF-α-mediated p65-NF-κB phosphorylation but reduced ERK1/2 phosphorylation. BE co-treatment further increased TNF-α-induced mRNA expression and secretion of NF-κB target genes, such as IL-6, IL-8, and MCP-1, while mRNA levels of ICAM-1 were reduced. CONCLUSIONS: BE co-treatment reduced IFN-γ-induced signal protein activation, pro-inflammatory gene expression, and cytokine secretion, whereas it enhanced TNF-α-induced responses. These findings suggest a distinct role for anthocyanins in modulating inflammatory responses that need to be further studied to fully understand anthocyanin-mediated effects.