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Myelodysplastic syndromes (MDS) represent a heterogeneous group of clonal stem cell disorders characterized by ineffective hematopoiesis frequently progressing into acute myeloid leukemia (AML), with emerging evidence implicating aberrant bone marrow (BM) microenvironment and inflammationrelated changes. 5-azacytidine (5-AC) represents standard MDS treatment. Besides inhibiting DNA/RNA methylation, 5-AC has been shown to induce DNA damage and apoptosis in vitro. To provide insights into in vivo effects, we assessed the proinflammatory cytokines alterations during MDS progression, cytokine changes after 5-AC, and contribution of inflammatory comorbidities to the cytokine changes in MDS patients. We found that IL8, IP10/CXCL10, MCP1/CCL2 and IL27 were significantly elevated and IL12p70 decreased in BM of MDS low-risk, high-risk and AML patients compared to healthy donors. Repeated sampling of the high-risk MDS patients undergoing 5-AC therapy revealed that the levels of IL8, IL27 and MCP1 in BM plasma were progressively increasing in agreement with in vitro experiments using several cancer cell lines. Moreover, the presence of inflammatory diseases correlated with higher levels of IL8 and MCP1 in low-risk but not in high-risk MDS. Overall, all forms of MDS feature a deregulated proinflammatory cytokine landscape in the BM and such alterations are further augmented by therapy of MDS patients with 5-AC.

All-trans-retinoic acid (atRA) is a potent ligand that regulates gene expression and is used to treat several skin disorders. Hyaluronic acid (HA) was previously conjugated with atRA (HA-atRA) to obtain a novel amphiphilic compound. HA-atRA forms micelles that incorporate hydrophobic molecules and facilitate their transport through the skin. The aim of this study was to determine the influence of HA-atRA on gene expression in skin cells and to compare it with that of unbound atRA. Gene expression was investigated using microarrays and a luciferase system with a canonical atRA promoter. HA-atRA upregulated gene expression similarly to atRA. However, HA-atRA activated the expression of cholesterol metabolism genes, unlike atRA. Further investigation using HPLC and filipin III staining suggested that the treated cells induced cholesterol synthesis to replenish the cholesterol removed from the cells by HA-atRA. HA modified with oleate (HA-C18:1) removed cholesterol from the cells similarly to HA-atRA, suggesting that the cholesterol removal stemmed from the amphiphilic nature of the two derivatives. HA-atRA induces retinoid signaling. Thus, HA-atRA could be used to treat skin diseases, such as acne and psoriasis, where the combined action of atRA signaling and anti-inflammatory cholesterol removal may be potentially beneficial.

Irritant damage to the permeability barrier elicits a cascade of responses that could be investigated by minimally invasive in vivo methods providing different information on biochemical and functional levels. Recent studies have shown that parallel to impairment of the barrier function and reduction of the natural moisturising factor (NMF), irritants such as the anionic detergent sodium lauryl sulfate (SLS) influence the corneocyte surface topography, investigated by atomic force microscopy and expressed by the Dermal Texture Index (DTI). To extend these findings, we investigated the early and late effects of different water soluble irritants on the barrier function, DTI, NMF and primary cytokine levels in healthy volunteers exposed to 60% N-propanol, 0.5% SLS, 0.15% sodium hydroxide, 2.0% acetic acid and occlusion with water in a controlled tandem repeated irritation test (TRIT) over 96 h. The irritant response was assessed by measuring erythema, transepidermal water loss (TEWL) and capacitance at baseline, 24 h and 96 h later; the cytokine levels, NMF and DTI were assessed in tape strips, collected at the same time points from the irritant-exposed and non-exposed sites. The magnitude of effects exerted by the irritants on the barrier integrity and properties, primary cytokine levels and DTI, found in the study, differed significantly, based on the chemical characteristics. The changes in DTI correlated with the NMF levels while being less influenced by inflammation. Though the observed differences may be influenced by the applied irritant concentration, our results confirm the need for a multi-parametric approach in the characterization of the irritant-specific barrier response and identification of sensitive outcome parameters for studying skin irritation in vivo.

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