Mesenchymal stem cells (MSCs) are, due to immunomodulatory characteristics, considered as novel agents in the treatment of immune-mediated acute liver failure. Although it is known that MSCs can regulate activation of T lymphocytes, their capacity to modulate function of neutrophils and natural killer T (NKT) cells, major interleukin (IL) 17-producing cells in acute liver injury, is still unknown. By using 2 well-established murine models of neutrophil and NKT cell-mediated acute liver failure (induced by carbon tetrachloride and α-galactoceramide), we investigated molecular and cellular mechanisms involved in MSC-mediated modulation of IL17 signaling during acute liver injury. Single intravenous injection of MSCs attenuate acute hepatitis and hepatotoxicity of NKT cells in a paracrine, indoleamine 2,3-dioxygenase (IDO)-dependent manner. Decreased levels of inflammatory IL17 and increased levels of immunosuppressive IL10 in serum, reduced number of interleukin 17-producing natural killer T (NKT17) cells, and increased presence of forkhead box P3 + IL10-producing natural killer T regulatory cells (NKTregs) were noticed in the injured livers of MSC-treated mice. MSCs did not significantly alter the total number of IL17-producing neutrophils, CD4+, and CD8 + T lymphocytes in the injured livers. Injection of mesenchymal stem cell-conditioned medium (MSC-CM) resulted with an increased NKTreg/NKT17 ratio in the liver and attenuated hepatitis in vivo and significantly reduced hepatotoxicity of NKT cells in vitro. This phenomenon was completely abrogated in the presence of IDO inhibitor, 1-methyltryptophan. In conclusion, the capacity of MSCs to alter NKT17/NKTreg ratio and suppress hepatotoxicity of NKT cells in an IDO-dependent manner may be used as a new therapeutic approach in IL17-driven liver inflammation. Liver Transplantation 23 1040-1050 2017 AASLD.

This study investigates molecular and cellular mechanisms involved in mesenchymal stem cell (MSC)-mediated modulation of IL-17 signaling during liver fibrosis. Mice received CCl (1 μl/g intraperitoneally) twice/week for 1 month. MSCs (1 × 10 ), or MSC-conditioned medium (MSC-CM), were intravenously injected 24 h after CCl and on every 7th day. Liver fibrosis was determined by macroscopic examination, histological analysis, Sirius red staining, and RT-PCR. Serum levels of cytokines, indoleamine 2,3-dioxygenase (IDO), and kynurenine were determined by ELISA. Flow cytometry was performed to identify liver-infiltrated cells. In vitro, CD4 T cells were stimulated and cultured with MSCs. 1-methyltryptophan was used for inhibition of IDO. MSCs significantly attenuated CCl -induced liver fibrosis by decreasing serum levels of inflammatory IL-17, increasing immunosuppressive IL-10, IDO, and kynurenine, reducing number of IL-17 producing Th17 cells, and increasing percentage of CD4 IL-10 T cells. Injection of MSC-CM resulted with attenuated fibrosis accompanied with the reduced number of Th17 cells in the liver and decreased serum levels of IL-17. MSC-CM promoted expansion of CD4 FoxP3 IL-10 T regulatory cells and suppressed proliferation of Th17 cells. This phenomenon was completely abrogated in the presence of IDO inhibitor. MSCs, in IDO-dependent manner, suppress liver Th17 cells which lead to the attenuation of liver fibrosis.

In this study the leaves and fruits of wild raspberry (Rubus idaeus L.) populations from the central Balkan region were examined to determine the level of secondary metabolites and related antioxidant activity, as well as biological activity, upon existing ethnobotanical evidence, primarily linked to gastrointestinal disorders. The values obtained for total phenols ranged from 59.68 to 96.83 mg GA g-1 and 24.29 to 38.71 mg GA g-1 in leaf and fruit extracts, respectively. The highest values of tannins and anthocyanins were determined for leaf extracts from a population of east Serbia at a level of 1.27 mg mL-1 and 9.00 mg mL-1. Antioxidant activity was evaluated by measuring the scavenging capacity of the extracts on DPPH. Higher antioxidant activity was detected in the leaf extracts than in the fruit extracts. Leaf and fruit extract were the most effective against Escherichia coli (ATCC 8739). Anticancer activity was studied on a human colorectal cancer cell line HCT-116. Leaf extracts exhibited anticancer activity with IC50/24 h 162.38 μg mL-1 and IC50/48 h 95.69 μg mL-1. Wild raspberry leaf and fruit extracts contain numerous secondary metabolites providing marked antioxidant, antimicrobial and anticancer activity.

Background:Dendritic cell (DC)-derived indolamine 2,3-dioxygenase (IDO) degrades tryptophan to kynurenine, which promotes conversion of inflammatory T cells in immunosuppressive regulatory T cells (Tregs). We analyzed the significance of the IDO:Treg axis for inducing and maintaining mucosal healing in ulcerative colitis (UC).Methods:Dextran sodium sulphate (DSS)-induced colitis in BALB/c mice (model for mucosal healing) and C57BL/6 mice (model for persistent disease) was used. Serum, fecal samples and colon-infiltrating immune cells of 65 patients with UC with mucosal healing or persistent colitis were analyzed.Results:Significantly higher serum levels of kynurenine and downregulated inflammatory cytokines were noticed in DSS-treated BALB/c mice compared with C57BL/6 mice. Increased IDO activity and attenuated capacity for antigen presentation and production of inflammatory cytokines, observed in BALB/c DCs, was followed by a significantly lower number of inflammatory T helper 1 (Th1) and Th17 cells and a notably increased number of Tregs in the colons of DSS-treated BALB/c mice. DCs and Tregs were crucially important for the maintenance of mucosal healing since their depletion aggravated colitis. Mucosal healing, followed by an increase in kynurenine and intestinal Tregs, was re-established when BALB/c DCs were transferred into DC-depleted or Treg-depleted DSS-treated BALB/c mice. This phenomenon was completely abrogated by the IDO inhibitor. Significantly higher serum and fecal levels of kynurenine, accompanied by an increased presence of intestinal Tregs, were noticed in patients with UC with mucosal healing and negatively correlated with disease severity, fecal calprotectin, colon-infiltrating interferon γ and interleukin-17-producing cells, serum and fecal levels of inflammatory cytokines.Conclusion:IDO-dependent expansion of endogenous Tregs should be further explored as a new approach for the induction and maintenance of mucosal healing in patients with UC.

Objective: Mortality has been shown to increase with heat waves. Serbia experienced the hottest heat wave in July 2007. In this study, we examined patterns of non-traumatic excess mortality in Belgrade during this event. Methods: The numbers of deaths observed during the 9-day heat wave were compared to those expected on the basis of mortality rates reported for the previous eight years and two following years. Excess mortality was analyzed by age, gender and cause of death. Results: There was a total of 167 excess deaths (38%) between 16 and 24 July. People aged 75 years and older accounted for 151 (90%) of all excess deaths. An increase of mortality among elderly was 76% in comparison to the baseline mortality. Excess female mortality was over two times higher than excess male mortality (54% : 23%). The biggest increase in mortality was from diabetes mellitus (286%), chronic kidney disease (200%), respiratory system diseases (73%), and nervous system diseases (67%). Cardiovascular and malignant neoplasms mortality accounted for the highest absolute numbers of excess deaths (77 and 49, respectively). There was no decrease in mortality in the 60-day period after the heat wave. Conclusions: There are several causes of an increase in heat-related mortality. The most vulnerable population group is the elderly females.