LRG1 promotes corneal angiogenesis and lymphangiogenesis in a corneal alkali burn mouse model

AIM:To investigate the potential effect and mechanism of leucine-richα-2-glycoprotein-1(LRG1)on corneal angiogenesis and lymphangiogenesis.METHODS:Corneal neovascularization and lymphatics were induced by establishing alkali burn mouse model.Immunofluorescence staining was performed to detect the location of LRG1 in cornea tissues and to verify the source of LRG1-positive cells.Corneal whole-mount staining for CD31(a panendothelial cell marker)and lymphatic endothelial hyluronan receptor-1(LYVE-1;lymphatic marker)was performed to detect the growth of blood and lymphatic vessels after local application of exogenous LRG1 protein or LRG1 si RNA.In addition,expressions of the proangiogenic vascular endothelial growth factor(VEGF)related proteins were detected using Western blot analysis.RESULTS:LRG1 was dramatically increased in alkali burned corneal stroma in both the limbal and central areas.LRG1-positive cells in the corneal stroma were mainly derived from Vimentin-positive cells.Local application ofexogenous LRG1 protein not only aggravated angiogenesis but also lymphangiogenesis significantly(P<0.01).LRG1 group upregulated the levels of VEGF and the vascular endothelial growth factor receptor(VEGFR)family when compared with the phosphate-buffered saline(PBS)control group.We also found that LRG1-specific si RNA could suppress corneal angiogenesis and lymphangiogenesis when compared with the scramble si RNA-treated group(P<0.01).CONCLUSION:LRG1 can facilitate corneal angiogenesis and lymphangiogenesis through heightening the stromal expression of VEGF-A,B,C,D and VEGFR-1,2,3;LRG1-specific si RNA can suppress corneal angiogenesis and lymphangiogenesis in corneal alkali burn mice.

Axonal growth inhibitors and their receptors in spinal cord injury:from biology to clinical translation

Axonal growth inhibitors are released during traumatic injuries to the adult mammalian central nervous system, including after spinal cord injury. These molecules accumulate at the injury site and form a highly inhibitory environment for axonal regeneration. Among these inhibitory molecules, myelinassociated inhibitors, including neurite outgrowth inhibitor A, oligodendrocyte myelin glycoprotein, myelin-associated glycoprotein, chondroitin sulfate proteoglycans and repulsive guidance molecule A are of particular importance. Due to their inhibitory nature, they represent exciting molecular targets to study axonal inhibition and regeneration after central injuries. These molecules are mainly produced by neurons, oligodendrocytes, and astrocytes within the scar and in its immediate vicinity. They exert their effects by binding to specific receptors, localized in the membranes of neurons. Receptors for these inhibitory cues include Nogo receptor 1, leucine-rich repeat, and Ig domain containing 1 and p75 neurotrophin receptor/tumor necrosis factor receptor superfamily member 19(that form a receptor complex that binds all myelin-associated inhibitors), and also paired immunoglobulin-like receptor B. Chondroitin sulfate proteoglycans and repulsive guidance molecule A bind to Nogo receptor 1, Nogo receptor 3, receptor protein tyrosine phosphatase σ and leucocyte common antigen related phosphatase, and neogenin, respectively. Once activated, these receptors initiate downstream signaling pathways, the most common amongst them being the Rho A/ROCK signaling pathway. These signaling cascades result in actin depolymerization, neurite outgrowth inhibition, and failure to regenerate after spinal cord injury. Currently, there are no approved pharmacological treatments to overcome spinal cord injuries other than physical rehabilitation and management of the array of symptoms brought on by spinal cord injuries. However, several novel therapies aiming to modulate these inhibitory proteins and/or their receptors are under investigation in ongoing clinical trials. Investigation has also been demonstrating that combinatorial therapies of growth inhibitors with other therapies, such as growth factors or stem-cell therapies, produce stronger results and their potential application in the clinics opens new venues in spinal cord injury treatment.

Antiphospholipid syndrome and its role in pediatric cerebrovascular diseases: A literature review

Antiphospholipid syndrome(APS)or Hughes syndrome is an acquired thromboinflammatory disorder.Clinical criteria of APS diagnosis are large-and small-vessel thrombosis as well as obstetric problems;laboratory criteria are the presence of antiphospholipid antibodies(lupus anticoagulant,anticardiolipin antibodies and anti-β2-glycoprotein-1).The presence of at least 1 clinical and 1 laboratory criterion allows definitive diagnosis of APS.Primary APS is diagnosed in patients without features of connective tissue disease;secondary APS is diagnosed in patients with clinical signs of autoimmune disease.A high frequency of catastrophic APS as well as a high tendency to evolve from primary APS to secondary syndrome during the course of lupus and lupus-like disease is a feature of pediatric APS.The most characteristic clinical presentation of APS in the pediatric population is venous thrombosis,mainly in the lower limbs,and arterial thrombosis causing ischemic brain stroke.Currently,no diagnostic criteria for pediatric APS exist,which probably results in an underestimation of the problem.Similarly,no therapeutic procedures for APS specific for children have yet been established.In the present literature review,we discussed data concerning APS in children and its role in cerebrovascular diseases,including pediatric arterial ischemic stroke,migraine and cerebral venous thrombosis.

Chemical control of receptor kinase signaling by rapamycin-induced dimerization

Membrane-localized leucine-rich repeat receptor kinases(LRR-RKs)sense diverse extracellular signals,and coordinate and specify cellular functions in plants.However,functional understanding and identification of the cellular signaling of most LRR-RKs remain a major challenge owing to their genetic redundancy,the lack of ligand information,and subtle phenotypes of LRR-RK overexpression.Here,we report an engineered rapamycin-inducible dimerization(RiD)receptor system that triggers a receptor-specific LRR-RK signaling independent of their cognate ligands or endogenous receptors.Using the RiD-receptors,we demonstrated that the rapamycin-mediated association of chimeric cytosolic kinase domains from the BRI1/BAK1 receptor/co-receptor,but not the BRI1/BRI1 or BAK1/BAK1 homodimer,is sufficient to activate downstream brassinosteroid signaling and physiological responses.Furthermore,we showed that the engineered RiD-FLS2/BAK1 could activate flagellin-22-mediated immune signaling and responses.Using the RiD system,we also identified the potential function of an unkmown orphan receptor in immune signaling and revealed the differential activities of SERK co-receptors of LRR-RKs.Our results indicate that the RiD method can serve as a synthetic biology tool for precise temporal manipulation of LRR-RK signaling and for understanding LRR-RK biology.