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  • We have not observed elevated cytokine levels in


    We have not observed elevated cytokine levels in non-infected naïve Dp10 mice, although elevated levels of pro-inflammatory cytokines have been reported in individuals with DS not suffering from an infection [10]. Beyond the fact that experimental mice are kept in an otherwise sterile environment untypical of normal human living conditions, as mentioned above, Dp10 mice are only trisomic for a fraction of the Hsa21 genes. Genes present on Hsa21 but lacking in Dp10 animals might for example promote oxidative stress, which is inherent to DS [1], [28], [29] and would further exacerbate inflammation and increase TRPM2-activation. Additionally, some Hsa21 genes not on Dp10’s transgene are crucial immune regulatory components, including four IFN receptor subunits, which are located on the Dp16 transgene. The dysregulated overexpression of the IFN receptors in DS is thought to be a major cause of developmental, cognitive and immunological abnormalities. DS can therefore be designated an interferonopathy, and a recent study has lent credential to this notion by demonstrating that the consistent gene expression signature in DS shows the hallmarks of the IFN signaling pathway [30]. The pleiotropic impact of IFN-Jak/Stat-signaling hyperactivation is well documented [31], [32] and could underlie many of the health conditions affecting people with DS, including increased incidence of leukemias, and of autoimmune disorders such as hypothyroidism, alopecia areata and type 1 diabetes [33], [34]. As Trpm2 overexpression in DS would promote expression of cytokines including IFNγ, Trpm2 Herboxidiene have the potential to aggravate the already existent hyperactivation of IFN-signaling in DS. As a consequence, increased Trpm2-mediated ion flux might be a significant contributor to conditions associated with DS. Pharmacological intervention strategies targeting the Jak/Stat pathway downstream of IFN-receptor activation are already well established and at the center of multiple existing and currently developing therapies. However, given the broad biological context of Jak/Stat signaling, the risks for side effects and toxicity remain a potential limitation. Trpm2, given its more restricted function as an amplifier of cytokine production and unique mode of activation through metabolic and oxidative stress, could represent an alternative target to dampen IFN-signaling with less potential side effects. This could be achieved either by influencing the activity of Trpm2 itself, or the production of its ligand activator, ADP-ribose. Future studies will need to reveal whether this approach could also be a promising avenue in the context of DS as the DS community is in need of novel therapeutic strategies to treat ailments and increase quality of life.
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    Introduction Non-alcoholic fatty liver disease (NAFLD) is one of the most prevalent chronic liver diseases worldwide [1]. NAFLD, defined as excessive lipid accumulation in the liver, ranges in severity from benign fatty liver to nonalcoholic steatohepatitis (NASH). NASH is characterized by oxidative stress, lipid peroxidation, fibrosis, and inflammation. NASH can progress to cirrhosis, the formation of pre-neoplastic nodules, and the development of hepatocellular carcinoma (HCC) [2]. Day and James (1998) have proposed a two-hit model of NAFLD pathogenesis [3]. The first hit is deposition of free fatty acids and triglycerides in hepatocytes (steatosis), and the second hit is the progression of steatosis to NASH. Both of these hits are accompanied by hepatic lipogenesis and increased oxidative stress and inflammation. Liver fibrosis occurs in most types of chronic liver diseases and involves excessive deposition of extracellular matrix (ECM) proteins [4]. Hepatic stellate cells (HSCs) are thought to play a central role in liver fibrosis [5], [6]. In response to injury and inflammatory stimuli, HSCs lose vitamin A-storing droplets and transdifferentiate into myofibroblasts with induction of α-smooth muscle actin [7]. Activated HSCs are highly proliferative and secrete fibrogenic mediators leading to excessive extracellular matrix deposition [8], [9]. Therefore, inhibiting HSC activation is a prime target for therapeutic intervention.