Whither State Immunity?: An Assessment of the Current State of the Law

Recent developments in the area of state immunity evidence a substantial influence on the future of the doctrine in international law. The author discusses in detail the European Convention on State Immunity and Additional Protocol of 1972, the United States Foreign Sovereign Immunities Act of 1976, the British State Immunity Act of 1978, and the Singapore State Immunity Act of 1979. He compares the four and makes suggestions about how they have individually and collectively affected the development of the doctrine

Fas-induced apoptosis in malnourished infants

Background: Malnutrition in children is frequently associated with an increased incidence of infection. Apoptosis of immune cells in undernourished organisms may cause an increase in the organism's susceptibility to diseases related to immune suppression. Lymphocyte apoptosis was described in malnutrition. The role of factor of apoptosis signal (fas,CD95) in apoptosis of lymphocyte populations in malnourished children is still unclear. Objective: This study investigated apoptosis in T lymphocytes in different types of malnutrition and the role of Fas in lymphocyte apoptosis and its relation to clinical and laboratory parameters of malnutrition. Study design: Sixty-three malnourished infants and children were compared to 27 healthy controls. Beside thorough history and clinical examination, laboratory investigations and flow cytometry assessment of T lymphocytes were done. The viability of T lymphocytes was determined by combination of fluorescence dye 7-amino actinomycin, CD95 and CD3. Results: There was significant increase in apoptotic T-cells in the patients compared to the controls. There was up-regulation of Fas expression in CD3+ cells. Furthermore CD3+/CD95+ cells were less viable than CD3+/CD95- cells of the patients and than CD3+/CD95+ cells of the controls. All the clinical and laboratory parameters of the studied patients showed no significant correlations with any of the apoptotic indices. Conclusion: Increased apoptosis in T lymphocytes in malnourished children may be the cause of the decrease in lymphocyte count in their peripheral blood. This in turn may be the cause of decreased cell mediated immunity and the more common occurrence of infection in such patients. Upregulation of Fas may be the cause of apoptosis in T lymphocytes in these malnourished children.Keywords: Fas, apoptosis, malnutrition, flow cytometry, infection, T lymphocytes.Egypt J Pediatr Allergy Immunol 2010;8(1):27-3

Thymoquinone Inhibits the CXCL12-Induced Chemotaxis of Multiple Myeloma Cells and Increases Their Susceptibility to Fas-Mediated Apoptosis

In multiple myeloma (MM), malignant plasma cells reside in the bone marrow, where they accumulate in close contact with stromal cells. The mechanisms responsible for the chemotaxis of malignant plasma cells are still poorly understood. Thus, we investigated the mechanisms involved in the chemotaxis of MDN and XG2 MM cell lines. Both cell lines strongly expressed CCR9, CXCR3 and CXCR4 chemokine receptors but only migrated toward CXCL12. Activation of CXCR4 by CXCL12 resulted in the association of CXCR4 with CD45 and activation of PLCβ3, AKT, RhoA, IκBα and ERK1/2. Using siRNA-silencing techniques, we showed CD45/CXCR4 association is essential for CXCL12-induced migration of MM cells. Thymoquinone (TQ), the major active component of the medicinal herb Nigella sativa Linn, has been described as a chemopreventive and chemotherapeutic compound. TQ treatment strongly inhibited CXCL12-mediated chemotaxis in MM cell lines as well as primary cells isolated from MM patients, but not normal PBMCs. Moreover, TQ significantly down-regulated CXCR4 expression and CXCL12-mediated CXCR4/CD45 association in MM cells. Finally, TQ also induced the relocalization of cytoplasmic Fas/CD95 to the membrane of MM cells and increased CD95-mediated apoptosis by 80%. In conclusion, we demonstrate the potent anti-myeloma activity of TQ, providing a rationale for further clinical evaluation

Thymoquinone decreases F-actin polymerization and the proliferation of human multiple myeloma cells by suppressing STAT3 phosphorylation and Bcl2/Bcl-XL expression

<p>Abstract</p> <p>Background</p> <p>Thymoquinone (TQ), the major active component of the medicinal herb Nigella sativa Linn., has been described as a chemopreventive and chemotherapeutic compound.</p> <p>Methods</p> <p>In this study, we investigated the effect of TQ on survival, actin cytoskeletal reorganization, proliferation and signal transduction in multiple myeloma (MM) cells.</p> <p>Results</p> <p>We found that TQ induces growth arrest in both MDN and XG2 cells in a dose- and time-dependent manner. TQ also inhibited CXC ligand-12 (CXCL-12)-mediated actin polymerization and cellular proliferation, as shown by flow cytometry. The signal transducer and activator of transcription (STAT) and B-cell lymphoma-2 (Bcl-2) signaling pathways may play important roles in the malignant transformation of a number of human malignancies. The constitutive activation of the STAT3 and Bcl-2 pathways is frequently observed in several cancer cell lines, including MM cells. Using flow cytometry, we found that TQ markedly decreased STAT3 phosphorylation and Bcl-2 and Bcl-_XLexpression without modulating STAT5 phosphorylation in MM cells. Using western blotting, we confirmed the inhibitory effect of TQ on STAT3 phosphorylation and Bcl-2 and Bcl-_XLexpression.</p> <p>Conclusions</p> <p>Taken together, our data suggests that TQ could potentially be applied toward the treatment of MM and other malignancies.</p

Maternal supplementation of diabetic mice with thymoquinone protects their offspring from abnormal obesity and diabetes by modulating their lipid profile and free radical production and restoring lymphocyte proliferation via PI3K/AKT signaling

BACKGROUND: Epidemiological studies have shown that the offspring of mothers who experience diabetes mellitus during pregnancy are seven times more likely to develop health complications than the offspring of mothers who do not suffer from diabetes during pregnancy. The present study was designed to investigate whether supplementation of streptozotocin (STZ)-induced diabetic pregnant mice with thymoquinone (TQ) during pregnancy and lactation improves the risk of developing diabetic complications acquired by their offspring. METHODS: Three groups of pregnant female mice were used: non-diabetic control dams (CD), diabetic dams (DD), and diabetic dams supplemented with TQ (DD + TQ) during pregnancy and lactation (n = 10 female mice in each group). RESULTS: Our data demonstrated a marked decrease in the number of neonates born to DD, and these neonates showed a marked increase in their mean body weight (macrosomic pups) compared to those born to CD and DD + TQ. The induction of diabetes during pregnancy and lactation resulted in macrosomic pups with several postpartum complications, such as a marked increase in their levels of blood glucose, free radicals, plasma pro-inflammatory cytokines (IL-1β, IL-6, and TNF-α), and lipids, and a tendency toward abnormal obesity compared to the offspring of CD. By contrast, macrosomic offspring born to DD exhibited a marked reduction in plasma cytokine levels (IL-2, -4 and -7), an obvious reduction in the number of circulating lymphocytes, decreased proliferation of superantigen (SEB)-stimulated lymphocytes and aberrant AKT phosphorylation. Interestingly, the supplementation of DD with TQ during pregnancy and lactation had an obvious and significant effect on the number and mean body weight of neonates. Furthermore, TQ significantly restored the levels of blood glucose, insulin, free radicals, plasma cytokines, and lipids as well as lymphocyte proliferation in the offspring. CONCLUSIONS: Our data suggest that the nutritional supplementation of DD with the natural antioxidant TQ during pregnancy and lactation protects their offspring from developing diabetic complications and preserves an efficient lymphocyte immune response later in life

Blocking Type I Interferon Signaling Rescues Lymphocytes from Oxidative Stress, Exhaustion, and Apoptosis in a Streptozotocin-Induced Mouse Model of Type I Diabetes

Elevated levels of type I interferon (IFN) during type 1 diabetes mellitus (T1D) are associated with a defective immune response. In the present study, we investigated whether blocking type I IFN signaling during streptozotocin- (STZ-) induced T1D in mice improves lymphocyte proliferation and escape from continuous apoptosis. Three groups of mice were examined: diabetic mice, type I IFN signaling-incompetent diabetic mice, and control nondiabetic mice. We first found that diabetes induction was accompanied by an elevation in the plasma levels of reactive oxygen species (ROS), hydroperoxide, malondialdehyde (MDN), and the proinflammatory cytokines IL-1α, IL-1β, IL-6, and CXCL10. Blocking type 1 IFN signaling in diabetic mice significantly decreased the levels of oxidative stress and proinflammatory cytokines. In addition, lymphocytes from diabetic mice exhibited a marked reduction in their proliferative capacity, increased apoptosis, upregulation of the exhaustion marker PD-1, and aberrant phosphorylation of STAT1, STAT2, AKT and IκB-α. Interestingly, following the blocking of type I IFN signaling in diabetic mice, the lymphocytes exhibited restored proliferative capacity, decreased apoptosis, normal expression of PD-1, and normal phosphorylation of STAT1, STAT2, AKT and IκB-α. Our data suggest that elevated levels of type I IFN during T1D trigger lymphocyte exhaustion and a defective lymphocyte-medicated immune response

Fetuin-A and Ghrelin Levels in Children with End Stage Renal Disease and the Effect of a Single Hemodialysis Session on Them

BACKGROUND: Fetuin-A and ghrelin have been implicated in cardiovascular diseases and mortality among end stage renal disease patients. The exact mechanisms have not been fully elucidated. There is robust data supporting an association between ghrelin and various cardiovascular conditions, and some common processes such as inflammation, oxidative stress, and endoplasmic reticulum stress have been implicated.AIM: This study was conducted to assay serum fetuin-A and ghrelin in chronic renal failure pediatric patients and to study changes in their level that may occur after a single hemodialysis.MATERIAL AND METHODS: Forty nine pediatric patients suffering from ESRD on maintenance hemodialysis (HD), 20 patients with chronic renal failure (CRF) not on dialysis and 35 healthy subjects as control group were included. The mean age of the study population was 10.58 ± 3.94, 10.62 ± 3.24 and 10.61 ± 3.97 years respectively. Serum fetuin-A and plasma acyl ghrelin levels were measured by using ELISA method.RESULTS: The present study revealed that predialysis serum fetuin-A level was significantly increased in pediatric HD patients compared with the normal population, while ghrelin levels were significantly reduced. Furthermore, serum levels of fetuin-A decreased significantly after a single HD session.CONCLUSION: Our study concluded that fetuin-A and acyl ghrelin may play a role in inflammatory process among HD pediatric patients which may account for cardiovascular insults and mortality but their use as biochemical markers among ESRD pediatric patients have limitations due to wide fluctuations