Polyunsaturated fatty acids (PUFAs) are normal constituents of the diet, but have properties different from other fatty acids (e.g., through generation of signaling molecules). N-3 PUFAs reduce cancer cell growth, but no unified mechanism has been identified. We show that docosahexaenoic acid (DHA; 22:6 n-3) causes extensive changes in gene expression patterns at mRNA level in the colon cancer cell line SW620. Early changes include unfolded protein response (UPR) and increased levels of phosphorylated eIF2α as verified at protein level. The latter is considered a hallmark of endoplasmic reticulum (ER) stress and is abundantly present already after 3 h. It may coordinate many of the downstream changes observed, including signaling pathways for cell cycle arrest/apoptosis, calcium homeostasis, cholesterol metabolism, ubiquitination, and proteasomal degradation. Also, eicosapentaenoic acid (EPA), but not oleic acid (OA), induced key mediators of ER stress and UPR at protein level. Accumulation of esterified cholesterol was not compensated for by increased total levels of cholesterol, and mRNAs for cholesterol biosynthesis as well as de novo synthesis of cholesterol were reduced. These results suggest that cytotoxic effects of DHA are associated with signaling pathways involving lipid metabolism and ER stress.

Glatiramer acetate (GA or Copaxone) is a drug used to treat experimental autoimmune encephalomyelitis in mice and multiple sclerosis in human. Here, we describe a new mechanism of action for this drug. GA enhanced the cytolysis of human NK cells against autologous and allogeneic immature and mature monocyte-derived dendritic cells (DCs). This drug reduced the percentages of mature DCs expressing CD80, CD83, HLA-DR or HLA-I. In contrast, it did not modulate the percentages of NK cells expressing NKG2D, NKp30, or NKp44. Nonetheless, anti-NKp30 or anti-CD86 inhibited GA-enhanced human NK cell lysis of immature DCs. Hence, CD86, and NKp30 are important for NK cell lysis of immature DCs, whereas CD80, CD83, HLA-DR and HLA-I are important for the lysis of mature DCs when GA is used as a stimulus. Further, GA inhibited the release of IFN-gamma 24 h but increased the release of TNF-alpha 48 h after incubation with NK cells.

AIM:To investigate the effects of exercise on healthy individuals of both genders. METHODS:This study lasted 6 years and involved about 800 healthy people. Individuals were divided into females and males and further sub-divided into two groups; in the first group individuals run (or skied in the winter time) and then rested for 3 h, whereas individuals in the second group intensely cycled for 5 min. The status of health was determined by measuring the sedimentation rate and the intensity of exercises by measuring the heart rate. Blood samples were collected before and after exercise. RESULTS:We observed that in the first group a significant increase of the total white blood cells, segmented neutrophils, band neutrophils, eosinophils and to a lesser extent lymphocytes but not monocytes in the blood circulation. However, all cell types were increased in the circulation after 5 min intense exercise. No differences in the pattern of cell increase were observed among the genders. Activated partial thromboplastin time (APTT) and D-dimer were also measured in the blood of individuals who cycled intensely for 5 min to determine the coagulation and fibrinolytic activities in the blood. APTT is reduced and D-dimer values significantly increased after intense exercise. However, APTT was statistically lower in males than females, whereas no differences in the D-dimer values were observed among the genders. CONCLUSION:Our results indicate that exercise whether leisure or strenuous affects leukocytosis and hemostasis in both genders. A major advantage of this study is the high numbers of individuals involved and the inclusion of both females and males values.

Introduction The immune system is composed of a network of cells and proteins that act in concert to defend the body against diseases. There is increasing evidence that key components of the innate immune system such as natural killer (NK) cells are instrumental in

The aims of this study are to examine the effect of sphingosine 1-phosphate (S1P) on IL-2-activated natural killer (NK) cell lysis of K562 tumor cells and immature dendritic cells (iDCs), and to investigate the mechanisms involved in S1P activity. Our results show that S1P protected K562 cells or iDCs from NK cell lysis, which was reversed by FTY720 and SEW2871, the antagonists of S1P(1). S1P did not modulate the expression of NKG2D, NKp30, NKp44 or CD158 on the surface of NK cells, and neither affected the expression of CD80, CD83, or CD86 on the surface of DCs. In contrast, it increased the expression of HLA-I and HLA-E on DCs, an activity that was inhibited by FTY720 or SEW2871. Similarly, the inhibitory effect of S1P for NK cell lysis of K562 cells was directed toward S1P(1) expressed on the tumor cells but not on NK cells. Further analysis indicates that NK cells secreted various cytokines and chemokines with various intensities: (1) low (IL-4, IL-6, IL-12, TNF-alpha and MCP-1); (2) intermediate (IL-1beta, IL-10, TGF-beta1, and IL-17A); (3) high (IFN-gamma, and MIP-1alpha); and (4) very high (MIP-1beta). S1P significantly reduced the release of IL-17A and IFN-gamma from NK cells, but this inhibition was S1P(1)-independent. These results indicate that S1P is an anti-inflammatory molecule, and that S1P(1) is important for the interaction among NK cells and tumor cells or DCs leading to up-regulation of HLA-I and HLA-E on the surface of DCs, but not in S1P inhibition of the release of inflammatory cytokines from NK cells. Further, the results suggest that FTY720 and SEW2871 may potentially be used as prophylactic and/or therapeutic drugs to treat cancer patients.