Inhibitory effects of Syzygium jambos extract on biomarkers of endothelial cell activation.

BACKGROUND: Disordered endothelial cell activation plays an important role in the pathophysiology of atherosclerosis, cancer, sepsis, viral infections, and inflammatory responses. There is interest in developing novel therapeutics to regulate endothelial cell function in atherothrombotic, metabolic, vascular, and hematological diseases. Extracts from leaves of the Syzygium jambos (L.) Alston (S. jambos) trees have been proposed to treat cardiovascular diseases and diabetes through unclear mechanisms. We investigated the effects of the S. jambos extract on biomarkers of endothelial dysfunction and immune responses in the human endothelial cell line, EA.hy926. METHODS: Leaves of S. jambos were collected, concocted and lyophilized. To study the effects of S. jambos on endothelial cell activation, we used the human endothelial cell line. IL-6 levels were measured using qPCR and ELISA. PDI activity was measured using Insulin Turbidity and Di-E-GSSG assays. CM-H2DCFDA was used to study ROS levels. Migration assay was used to study S. jambos effect on ex vivo human polymorphonuclear and human mononuclear cells. RESULTS: Our results show that incubation of EA.hy926 cells with ET-1 led to a 6.5 ± 1.6 fold increase in IL-6 expression by qPCR, an event that was blocked by S. jambos. Also, we observed that ET-1 increased extracellular protein disulfide isomerase (PDI) activity that was likewise dose-dependently blocked by S. jambos (IC50 = 14 µg/mL). Consistent with these observations, ET-1 stimulated ex vivo human polymorphonuclear and mononuclear cell migration that also was dose-dependently blocked by S. jambos. In addition, ET-1 stimulation led to significant increases in ROS production that were sensitive to S. jambos. CONCLUSION: Our results suggest that the S. jambos extract represents a novel cardiovascular protective pharmacological approach to regulate endothelial cell activation, IL-6 expression, and immune-cell responses.

Invasive pneumococcal infections in children following transplantation in the pneumococcal conjugate vaccine era.

BACKGROUND: Pediatric recipients of hematopoietic stem cell and solid organ transplants are at increased risk of invasive pneumococcal infections (IPI). Data on IPI in this population are scarce. To our knowledge, this is the first study describing the epidemiology of IPI among pediatric transplant recipients in the pneumococcal conjugate vaccine (PCV) era. METHODS: We identified transplant recipients with IPI at 8 children's hospitals in the U.S. from our surveillance database (2000-2014). Pneumococcal isolates were collected prospectively. Serotyping and antibiotic susceptibility were performed in a central laboratory. Categorical variables were analyzed by Fisher's exact test and continuous variables with nonparametric tests. Indirect cohort study design was used to calculate vaccine effectiveness. RESULTS: We identified 65 episodes of IPI in transplant recipients. Recurrent IPI was observed in 10% of transplant recipients. The IPI crude incidence rate in solid organ transplant recipients was higher than in the general population. Most IPI episodes occurred >6 months after transplantation. Bacteremia and pneumonia were the most common presentations. Meningitis was unusual. No case fatalities were observed. Serotype 19A was the most common serotype (n=10), followed by 6C (n=7). In 2010-2014, 37% of IPI was caused by PCV13 serotypes. Four cases of vaccine breakthrough were identified. Most isolates were susceptible to penicillin and ceftriaxone. Pneumococcal conjugate and polysaccharide immunization rates were low. CONCLUSION: Pediatric transplant recipients remain at increased risk of IPI in the vaccine era. Most cases presented as a late post-transplant infection. The interval between transplantation and IPI may allow adequate time for pneumococcal immunization.

Effects of Egb 761 on bone mineral density, bone microstructure, and osteoblast function: Possible roles of quercetin and kaempferol.

The effects of standardized and concentrated extract of Ginkgo biloba, Egb 761, were studied on estrogen deficiency-induced bone loss in ovariectomized (OVx) rats rendered osteopenic. Upon osteopenia development, Egb 761 was administered at a dose of 100mgkg(?1)day(?1) by oral gavage to OVx rats whereas control group received vehicle. Following 5 weeks of treatment, the OVx+Egb 761 group (n=12) of rats exhibited significantly higher whole body BMD and lower bone turnover markers (serum alkaline phosphatase and osteocalcin) than OVx rats that were given vehicle (n=12). BMD levels in excised bones were also found to be higher in both trabecular (most robustly in lumbar vertebrae) and cortical bones of OVx+Egb 761 compared with OVx+vehicle group. Egb 761 did not exhibit estrogen agonistic activity at the uterine level. Microcomputed tomography demonstrated that OVx+Egb 761 group had better bone microarchitectural parameters compared with OVx+vehicle group. Moreover, OVx+Egb 761 group had higher femoral mRNA levels of osterix, type I collagen and osteocalcin compared with OVx+vehicle group. Determination of levels of three flavonoids of Egb 761, that are known to have bone conserving property, in serum and bone marrow suggests that kaempferol and quercetin, and not rutin, likely mediate the beneficial actions observed with Egb 761 treatment. These results show for the first time that oral administration of Egb 761 restores bone mass in aged OVx rats.

Arginine supplementation of sickle transgenic mice reduces red cell density and Gardos channel activity.

Nitric oxide (NO), essential for maintaining vascular tone, is produced from arginine by nitric oxide synthase. Plasma arginine levels are low in sickle cell anemia, and it is reported here that low plasma arginine is also found in our sickle transgenic mouse model that expresses human alpha, human beta(S), and human beta(S-Antilles) and is homozygous for the mouse beta(major) deletion (S+S-Antilles). S+S-Antilles mice were supplemented with a 4-fold increase in arginine that was maintained for several months. Mean corpuscular hemoglobin concentration (MCHC) decreased and the percent high-density red cells was reduced. Deoxy K(+) efflux is characteristic of red cells in sickle cell disease and contributes to the disease process by increasing the MCHC and rendering the cells more susceptible to polymer formation. This flux versus the room air flux was reduced in S+S-Antilles red cells from an average value of 1.6 +/- 0.3 mmol per liter of red cells x minute (FU) in nonsupplemented mice to 0.9 +/- 0.3 FU (n = 4, P < .02, paired t test) in supplemented mice. In room air, V(max) of the Ca(++)-activated K(+) channel (Gardos) was reduced from 4.1 +/- 0.6 FU (off diet) to 2.6 +/- 0.4 FU (n = 7 and 8, P < .04, t test) in arginine-supplemented mice versus clotrimazole. In conclusion, the major mechanism by which arginine supplementation reduces red cell density (MCHC) in S+S-Antilles mice is by inhibiting the Ca(++)-activated K(+) channel.