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Patients with advanced congestive heart failure (CHF) or chronic kidney disease (CKD) often have increased angiotensin II (Ang II) levels and cachexia. Ang II infusion in rodents causes sustained skeletal muscle wasting and decreases muscle regenerative potential through Ang II type 1 receptor (AT1R)-mediated signaling, likely contributing to the development of cachexia in CHF and CKD. However, the potential role of Ang II type 2 receptor (AT2R) signaling in skeletal muscle physiology is unknown. We found that AT2R expression was increased robustly in regenerating skeletal muscle after cardiotoxin (CTX)-induced muscle injury in vivo and differentiating myoblasts in vitro, suggesting that the increase in AT2R played an important role in regulating myoblast differentiation and muscle regeneration. To determine the potential role of AT2R in muscle regeneration, we infused C57BL/6 mice with the AT2R antagonist PD123319 during CTX-induced muscle regeneration. PD123319 reduced the size of regenerating myofibers and expression of the myoblast differentiation markers myogenin and embryonic myosin heavy chain. On the other hand, AT2R agonist CGP42112 infusion potentiated CTX injury-induced myogenin and embryonic myosin heavy chain expression and increased the size of regenerating myofibers. In cultured myoblasts, AT2R knockdown by siRNA suppressed myoblast differentiation marker expression and myoblast differentiation via up-regulation of phospho-ERK1/2, and ERK inhibitor treatment completely blocked the effect of AT2R knockdown. These data indicate that AT2R signaling positively regulates myoblast differentiation and potentiates skeletal muscle regenerative potential, providing a new therapeutic target in wasting disorders such as CHF and CKD.

Angiogenesis is a hallmark of tumor development and metastasis and now a validated target for cancer treatment. We previously reported that a novel dimer peptide (apoEdp) derived from the receptor binding region of human apolipoprotein E (apoE) inhibits virus-induced angiogenesis. However, its role in tumor anti-angiogenesis is unknown. This study demonstrates that apoEdp has anti-angiogenic property in vivo through reduction of tumor growth in a mouse model and ocular angiogenesis in a rabbit eye model. Our in vitro studies show that apoEdp inhibits human umbilical vein endothelial cell proliferation, migration, invasion and capillary tube formation. We document that apoEdp inhibits vascular endothelial growth factor-induced Flk-1 activation as well as downstream signaling pathways that involve c-Src, Akt, eNOS, FAK, and ERK1/2. These in vitro data suggest potential sites of the apoE dipeptide inhibition that could occur in vivo. This is the first evidence that a synthetic dimer peptide mimicking human apoE has anti-angiogenesis functions and could be an anti-tumor drug candidate.

Treatment of diseases of the posterior segment of the eye, such as age-related macular degeneration, cytomegalovirus retinitis, diabetic retinopathy, posterior uveitis and retinitis pigmentosa, requires novel drug delivery systems that can overcome the many barriers for efficacious delivery of therapeutic drug concentrations. This challenge has prompted the development of biodegradable and nonbiodegradable sustained-release systems for injection or transplantation into the vitreous as well as drug-loaded nanoparticles, microspheres and liposomes. These drug delivery systems utilize topical, systemic, subconjunctival, intravitreal, transscleral and iontophoretic routes of administration. The focus of research has been the development of methods that will increase the efficacy of spatiotemporal drug application, resulting in more successful therapy for patients with posterior segment diseases. This article summarizes recent advances in the research and development of drug delivery methods of the posterior chamber of the eye, with an emphasis on the use of implantable devices as well as micro- and nanoparticles.

Although the importance of human apolipoprotein E (apoE) in vascular diseases has clearly been established, most of the research on apoE has focused on its role in cholesterol metabolism. In view of the observation that apoE and its functional domains impact extracellular matrix (ECM) remodeling, we hypothesized that apoE could also confer protection against ECM degradation by mechanisms independent of its role in cholesterol and lipoprotein transport. The ECM degrading enzyme, heparanase, is secreted by cells as pro-heparanase that is internalized through low-density lipoprotein (LDL) receptor-related protein-1 (LRP-1) to become enzymatically active. Both apoE and pro-heparanase bind the LRP-1. We further hypothesized that an apoE mimetic peptide (apoEdp) would inhibit the production of active heparanase by blocking LRP-1-mediated uptake of pro-heparanase and thereby decrease degradation of the ECM. To test this hypothesis, we induced the expression of heparanase by incubating human retinal endothelial cells (hRECs) with high glucose (30 mM) for 72 hours. We found that elevated expression of heparanase by high glucose was associated with increased shedding of heparan sulfate (ΔHS) and the tight junction protein occludin. Treatment of hRECs with 100 µM apoEdp in the presence of high glucose significantly reduced the expression of heparanase, shedding of ΔHS, and loss of occludin as detected by Western blot analysis. Either eye drop treatment of 1% apoEdp topically 4 times a day for 14 consecutive days or intraperitoneal injection (40 mg/kg) of apoEdp daily for 14 consecutive days in an in vivo mouse model of streptozotocin-induced diabetes inhibited the loss of tight junction proteins occludin and zona occludin- 1 (ZO-1). These findings imply a functional relationship between apoE and endothelial cell matrix because the deregulation of these molecules can be inhibited by a short peptide derived from the receptor-binding region of apoE. Thus, strategies targeting ECM-degrading enzymes could be therapeutically beneficial for treating diabetic retinopathy.

Purpose:To present a review supporting and refuting evidence from mouse, rabbit, nonhuman primate, and human studies of herpes simplex virus type 1 (HSV-1) concerning corneal latency.Methods:More than 50 research articles on HSV-1 published in peer-reviewed journals were examined.Results:Infectious