In many studies for chemoembolization of hepatocellular carcinoma, the Lipiodol emulsion preparation protocols, especially the mixing steps, were unclear or even unrevealed at all. However, doxorubicin (DOX) release may depend on the composition and volume ratio (Lipiodol to DOX solution) of a Lipiodol emulsion. Therefore, we conducted a preclinical study to compare in-vitro drug release and in-vivo pharmacokinetics of DOX from diverse Lipiodol emulsions and drug-eluting beads (DEBs) and to compare the tumor response in a rabbit VX2 carcinoma model. DOX release profiles of four types of Lipiodol emulsions with different media (normal saline or Pamiray as an iodinated contrast medium), volume ratio (Lipiodol to DOX solution), and DEBs were investigated in-vitro. For the in-vivo study, 15 rabbits bearing VX2 carcinoma in the liver were treated with 4∶1 volume ratio Lipiodol emulsion (group A), 1∶1 volume ratio Lipiodol emulsion (group B), and DEBs (group C) chemoembolization. Blood and tissue sampling was conducted to evaluate DOX concentration in plasma and tissues, histological changes, and liver toxicity. The most stable emulsion was formed with Pamiray (including DOX) at a 4∶1 volume ratio. The AUC value of group A was significantly lower than that of group B (p = 0.003) but comparable to that of group C (p = 0.071). The Cmax value of group A was significantly different compared with those of group B (p = 0.004) and C (p = 0.015). The tissue drug concentration in group A was comparable to that in group C (p = 0.251). No viable tumor was detected in rabbits of group A and B. In group C, viable tumor less than 10% was seen in two of the five rabbits. There were no significant differences in liver enzyme levels after the procedure. In conclusion, DOX release and pharmacokinetics of presented emulsion systems depend substantially on their composition. Therefore, Lipiodol emulsion type should be considered when interpreting data and designing new studies dealing with chemoembolization.

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Preconditioning with inflammatory cytokines has improved mesenchymal stem cells characteristics, including differentiation and immunomodulating functions. In this study, we developed a preconditioning combination strategy using interleukin‐1beta (IL‐1β) and interferon‐gamma (IFN‐γ) to enhance the immuneregulatory ability of human umbilical cord blood‐derived mesenchymal stem cells (hUCB‐MSCs). Our results showed that hUCB‐MSCs preconditioned with IL‐1β and IFN‐γ (primed hUCB‐MSCs) created a statistically significant decrease in peripheral blood mononuclear cell proliferation, indicating that their immunosuppressive ability was increased. The secretion of PGE2, cyclooxygenase 2 mRNA expression, and indoleamine 2,3‐dioxygenase (IDO) mRNA expression in primed hUCB‐MSCs was significantly higher than those in the untreated hUCB‐MSCs or the IL‐1β or IFN‐γ only treated hUCB‐MSCs. When inhibitors of IDO and PGE2 were treated, peripheral blood mononuclear cell proliferation, which is inhibited by primed hUCB‐MSCs, was recovered. We found that Th1 T cell differentiation was also inhibited by PGE2 and IDO in the primed hUCB‐MSCs, and Tregs differentiation was increased by PGE2 and IDO in the primed hUCB‐MSCs. Furthermore, the primed hUCB‐MSCs as well as supernatants increase CD4+ T cells migration. We demonstrated the therapeutic effects of primed hUCB‐MSCs in dextran sulfate sodium‐induced colitis model. In conclusion, we have demonstrated that primed hUCB‐MSCs simultaneously enhance PGE2 and IDO and greatly improve the immunoregulatory capacity of MSCs, and we have developed an optimal condition for pretreatment of MSCs for the treatment of immune diseases. Our results raise the possibility that the combination of PGE2 and IDO could be therapeutic mediators for controlling immunosuppression of MSCs.

Human mesenchymal stem cells (MSCs) are promising therapeutics for autoimmune diseases due to their immunomodulatory effects. In particular, human umbilical cord blood-derived MSCs (hUCB-MSCs) have a prominent therapeutic effect on atopic dermatitis (AD). However, the underlying mechanism is unclear. This study investigated the role of transforming growth factor-beta (TGF-β) in the therapeutic effect of hUCB-MSCs on AD. Small interfering RNA (siRNA)-mediated depletion of TGF-β disrupted the therapeutic effect of hUCB-MSCs in a mouse model of AD by attenuating the beneficial changes in histopathology, mast cell infiltration, tumor necrosis factor-alpha (TNF-α) expression, and the serum IgE level. To confirm that hUCB-MSCs regulate secretion of TNF-α, we investigated whether they inhibit TNF-α secretion by activated LAD2 cells. Coculture with hUCB-MSCs significantly inhibited secretion of TNF-α by LAD2 cells. However, this effect was abolished by siRNA-mediated depletion of TGF-β in hUCB-MSCs. TNF-α expression in activated LAD2 cells was regulated by the extracellular signal-related kinase signaling pathway and was suppressed by TGF-β secreted from hUCB-MSCs. In addition, TGF-β secreted by hUCB-MSCs inhibited maturation of B cells. Taken together, our findings suggest that TGF-β plays a key role in the therapeutic effect of hUCB-MSCs on AD by regulating TNF-α in mast cells and maturation of B cells.atopic dermatitis, IgE, mast cells, transforming growth factor-beta, tumor necrosis factoralpha, umbilical cord blood-derived mesenchymal stem cells | INTRODUCTIONAtopic dermatitis (AD) is a chronic allergic skin disorder associated with a delayed-type hypersensitivity reaction. The occurrence of AD is associated with various factors such as genetic predisposition, environmental factors, and immunological abnormalities. AD is classified as type 1 hypersensitivity according to the Gell and Coombs classification and is characterized by an allergic reaction triggered via Th2 signaling; however, the pathogenesis of AD is complex and not fully understood. [1][2][3][4][5] AD was recently found to be a much more heterogeneous disease than previously thought, with additional activation of the Th22, Th17/interleukin (IL)-23, and Th1 cytokine pathways depending on the disease subtype. 6 Hwan hee Park, Seunghee Lee, and Yeonsil Yu contributed equally to this work.