Thrombospondin Plays a Vital Role in the Immune Privilege of the Eye

Purpose: The role of thrombospondin (TSP)-1 in TGF-β activation and T-cell suppression was studied in the retinal pigment epithelial (RPE) cells, a monolayer of pigmented cells that line the subretinal space, an immune-privileged site in the eye. Methods: Posterior eyecups were prepared by excising the anterior segment, lens, and retina from enucleated eyes of C57BL/6, thrombospondin-1 knockout (TSP-1KO), and TGF-β2 receptor II double-negative (TGF-β2 RII DN) mice, leaving behind a healthy monolayer of RPE resting on choroid and sclera. Serum-free medium was added to these RPE eyecups, and, after various time intervals, supernatants (SNs) were removed and tested. Results: SNs of an ex vivo culture of RPE cells from C57BL/6 mice were shown to inhibit both antigen and anti-CD3 activation of T cells, partially due to constitutive production of TGF-β and to the ability of RPE to activate the latent form of TGF-β. Activation of TGF-β was entirely dependent on TSP-1, also produced by RPE. SNs of RPE from TSP-1KO mice failed to inhibit T-cell activation. Ovalbumin (OVA)-specific delayed hypersensitivity (DH) was not impaired when OVA was injected either into the subretinal space or into the anterior chamber of TSP-1KO mice before OVA immunization. Moreover, experimental autoimmune uveoretinitis was significantly more intense in eyes of TSP-1KO mice and failed to undergo spontaneous resolution unlike wild-type mice. Conclusions: Production of both TSP-1 and active TGF-β by RPE is essential to the creation and maintenance of immune privilege in the subretinal space and that the immune privilege limits the severity and duration of retinal inflammation due to autoimmunity.     

A National Experience on Physical Activity Initiatives for Adolescent Girls and their Mothers: CASPIAN Study

Objective

To provide a low-cost and simple model of culturally-appropriate and low cost facilities for improvement of physical activity for girls and their mothers through an after-school program and to determine the changes in anthropometric indexes after this trial.

Methods

This national study was conducted in 2006-2007 in 7 provinces with different socioeconomic situations in Iran. Female students who studied in the 7^th through 10^th grade and their mothers were selected by random cluster sampling. In each province, 24 sessions of after-school aerobic physical activity were held for 90 minutes, two days a week, and 3 months long at school sites in the afternoon.

Findings

The study comprised 410 participants (204 mothers and 206 daughters), with a mean age of 15.86±1.01 and 40.71±6.3 years in girls and their mothers, respectively. The results of the focus group discussions showed that in general, both mothers and daughters were satisfied from the program and found it feasible and successful. After the trial, the indexes of generalized and abdominal obesity improved significantly both in girls and in their mothers (P-value <0.0001 for weight, body mass index and waist circumference).

Conclusion

Our findings may provide a low-cost and simple effective model of motivation for physical activity with targeted interventions for girls and their mothers. We suggest that the success of this trial might be a result of bonding and accompaniment of mothers and daughters. Such model can be integrated in the existing health and education systems to increase the physical activity level.     

Synthesis, molecular docking study, and anticancer activity of triaryl-1,2,4-oxadiazole

This study describes synthesis of a new group of triaryl-1,2,4-oxadiazole derivatives and their anticancer activities. The target compounds were prepared from reaction of different imines and 4-substituted benzohydroxyiminoyl chlorides. All the synthesized compounds were screened for antiproliferative activities against MCF7 and K562 cell lines using MTT assay at 50-μM concentration. Four compounds that showed more than 50 % cytotoxicity were selected for determination of IC₅₀. Out of these, 6c-1y showed remarkable inhibitory cytotoxicity activity against MCF7 and K562 cell lines with IC₅₀ 6.50 and 21.66 μM, respectively. A molecular modeling study where 6c-1y was docked in the binding site of COX-2 showed a 2.3-Å hydrogen bond forming via hydroxyl group of Ser516 residue and oxygen of central oxadiazole ring and triaryl moiety of 6c-1y oriented toward the hydrophobic pockets of COX-2. Our data indicate that these derivatives may present promising chemotherapeutic agents, possibly targeting COX-2 pathway.     

Soluble vascular endothelial growth factor receptor-3 suppresses allosensitization and promotes corneal allograft survival

Purpose

To investigate the effect of VEGF-C and VEGF-D blockade via soluble VEGFR-3 (sVEGFR-3) on T cell allosensitization, corneal neovascularization, and transplant survival.

Methods

Corneal intrastromal suture placement and allogeneic transplantation were performed on BALB/c mice to evaluate the effect of sVEGFR-3 on corneal neovascularization. Soluble VEGFR-3 trap was injected intraperitoneally to block VEGF-C/D (every other day starting the day of surgery). Immunohistochemical staining of corneal whole mounts was performed using anti-CD31 (PECAM-1) and anti-LYVE-1 antibodies to quantify the levels of hem- and lymphangiogenesis, respectively. Mixed lymphocyte reaction (MLR) was performed to assess indirect and direct host T cell allosensitization and the frequencies of IFN-γ-producing T cells in the draining lymph nodes were assessed using flow cytometry. Graft opacity and survival was evaluated by slit-lamp biomicroscopy.

Results

Treatment with sVEGFR-3 resulted in a significant blockade of lymphangiogenesis 2 weeks post-transplantation and significantly prolonged corneal allograft survival compared to the control group at 8 weeks post-transplantation (87.5 % vs. 50 %), and this was associated with significant reduction in the frequencies of allosensitized T cells and decreased frequencies of IFN-γ–producing CD4 T cells.

Conclusions

Soluble VEGFR-3 suppresses corneal lymphangiogenesis and allograft rejection and may offer a viable therapeutic modality for corneal neovascularization and corneal transplantation.     

Intralipid prevents and rescues fatal pulmonary arterial hypertension and right ventricular failure in rats

Pulmonary arterial hypertension (PAH) is characterized by pulmonary vascular remodeling leading to right ventricular (RV) hypertrophy and failure. Intralipid (ILP), a source of parenteral nutrition for patients, contains γ-linolenic acid and soy-derived phytoestrogens that are protective for lungs and heart. We, therefore, investigated the therapeutic potential of ILP in preventing and rescuing monocrotaline-induced PAH and RV dysfunction. PAH was induced in male rats with monocrotaline (60 mg/kg). Rats then received daily ILP (1 mL of 20% ILP per day IP) from day 1 to day 30 for prevention protocol or from day 21 to day 30 for rescue protocol. Other monocrotaline-injected rats were left untreated to develop severe PAH by day 21 or RV failure by approximately day 30. Saline or ILP-treated rats served as controls. Significant increase in RV pressure and decrease in RV ejection fraction in the RV failure group resulted in high mortality. Therapy with ILP resulted in 100% survival and prevented PAH-induced RV failure by preserving RV pressure and RV ejection fraction and preventing RV hypertrophy and lung remodeling. In preexisting severe PAH, ILP attenuated most lung and RV abnormalities. The beneficial effects of ILP in PAH seem to result from the interplay of various factors, among which preservation and/or stimulation of angiogenesis, suppression and/or reversal of inflammation, fibrosis and hypertrophy, in both lung and RV, appear to be major contributors. In conclusion, ILP not only prevents the development of PAH and RV failure but also rescues preexisting severe PAH.