The role of HGF/c-MET signaling pathway in lymphoma

Inappropriate activation of c-mesenchymal-epithelial transition (MET), the receptor tyrosine kinase (RTK) for hepatocyte growth factor (HGF), has been implicated in tumorigenesis and represented a promising therapeutic target for developing anticancer agents. In contrast to other solid tumors, there are limited data describing the functional role of HGF/c-MET signaling pathway in lymphoma. In the current review, we summarize recent findings about the expression, cellular mechanisms/functions, and therapeutic application of HGF/c-MET in different types of lymphoma, especially B cell lymphoma, T and NK cell lymphoma, and Hodgkin lymphoma. We also discuss the existing problems and future directions about studying the HGF/c-MET pathway in lymphoma cells.     

Decreased Brain Levels of Vitamin B12 in Aging,Autism and Schizophrenia

Many studies indicate a crucial role for the vitamin B₁₂ and folate-dependent enzyme methionine synthase (MS) in brain development and function, but vitamin B₁₂ status in the brain across the lifespan has not been previously investigated. Vitamin B₁₂ (cobalamin, Cbl) exists in multiple forms, including methylcobalamin (MeCbl) and adenosylcobalamin (AdoCbl), serving as cofactors for MS and methylmalonylCoA mutase, respectively. We measured levels of five Cbl species in postmortem human frontal cortex of 43 control subjects, from 19 weeks of fetal development through 80 years of age, and 12 autistic and 9 schizophrenic subjects. Total Cbl was significantly lower in older control subjects (> 60 yrs of age), primarily reflecting a >10-fold age-dependent decline in the level of MeCbl. Levels of inactive cyanocobalamin (CNCbl) were remarkably higher in fetal brain samples. In both autistic and schizophrenic subjects MeCbl and AdoCbl levels were more than 3-fold lower than age-matched controls. In autistic subjects lower MeCbl was associated with decreased MS activity and elevated levels of its substrate homocysteine (HCY). Low levels of the antioxidant glutathione (GSH) have been linked to both autism and schizophrenia, and both total Cbl and MeCbl levels were decreased in glutamate-cysteine ligase modulatory subunit knockout (GCLM-KO) mice, which exhibit low GSH levels. Thus our findings reveal a previously unrecognized decrease in brain vitamin B₁₂ status across the lifespan that may reflect an adaptation to increasing antioxidant demand, while accelerated deficits due to GSH deficiency may contribute to neurodevelopmental and neuropsychiatric disorders.     

Ligand binding to anti-cancer target CD44 investigated by molecular simulations

CD44 is a cell-surface glycoprotein and receptor for hyaluronan, one of the major components of the tumor extracellular matrix. There is evidence that the interaction between CD44 and hyaluronan promotes breast cancer metastasis. Recently, the molecule F-19848A was shown to inhibit hyaluronan binding to receptor CD44 in a cell-based assay. In this study, we investigated the mechanism and energetics of F-19848A binding to CD44 using molecular simulation. Using the molecular mechanics/Poisson Boltzmann surface area (MM-PBSA) method, we obtained the binding free energy and inhibition constant of the complex. The van der Waals (vdW) interaction and the extended portion of F-19848A play key roles in the binding affinity. We screened natural products from a traditional Chinese medicine database to search for CD44 inhibitors. From combining pharmaceutical requirements with docking and molecular dynamics simulations, we found ten compounds that are potentially better or equal to the F-19848A ligand at binding to CD44 receptor. Therefore, we have identified new candidates of CD44 inhibitors, based on molecular simulation, which may be effective small molecules for the therapy of breast cancer.     

Internal Asymmetric Plasmonic Slot Waveguide for Third Harmonic Generation with Large Fabrication Tolerance

We propose an internal asymmetric plasmonic slot waveguide (IAPSW) containing two different materials in the slot region for third harmonic generation (THG) from 2.25 μm. In the IAPSW, the required phase matching condition is satisfied between the 0th-order mode at the fundamental frequency and 1st-order mode at the third harmonic frequency. By choosing an appropriate slot geometry and materials, the third harmonic electric field distribution can be engineered to significantly enhance the nonlinear overlap coefficient for THG. According to our simulation, a conversion efficiency up to 0.67 % with 1 W pump power is predicted within a ～10 μm IAPSW. Additionally, the waveguide shows large fabrication tolerance in terms of geometry parameters. The proposed waveguide can find potential applications for high-speed all-optical signal processing.     

Interactive actions of prostaglandin and epidermal growth factor to enhance proliferation of granulosa cells from chicken prehierarchical follicles

The interactive actions of prostaglandin (PG) and epidermal growth factor (EGF) on proliferation of granulosa cells was investigated in prehierarchical small yellow follicles (SYF) of laying hens. The granulosa layers were dispersed into single cells by 12.5 microg/ml collagenase. After 16 h pre-incubation in 0.5% fetal calf serum-supplemented medium, the medium was replaced with serum-free medium. Immunocytochemical staining showed that granulosa cells expressed EGF and its receptor, and their expression was increased by PGE(1) (1-100 ng/ml) or forskolin (10(-7) to 10(-5)M) treatments. EGF receptor was also induced by its ligand EGF. The specific prostaglandin synthase inhibitors SC560 (for COX-1) and NS398 (for COX-2) suppressed EGF-stimulated increase of the granulosa cell number. Furthermore, the effect of EGF was confirmed by the immunocytochemical staining of the proliferating cell nuclear antigen in granulosa cells. Though EGF promoted the expression of both COX-1 and COX-2, the rescue experiment indicated that combined treatment of PGE(1) showed better rescuing effect on NS398 inhibition than SC560 at 10(-6)M, which implies COX-2 plays the predominant role in mediating EGF action. The above results indicate that reciprocal stimulation of intracellular PG and EGF production may enhance proliferation of granulosa cells, hence to facilitate development of chicken prehierarchical follicles.     

Vascular endothelial growth factor: biology and therapeutic applications

While the development of anti-angiogenic therapy, as it pertains to cancer treatment, may still be in its infancy relative to well-established modalities such as chemotherapy, radiation, and surgery, major strides made in the past several decades have allowed translation of basic science discoveries in this field into clinical reality. The discovery of key molecular modulators of angiogenesis, notably vascular endothelial growth factor (VEGF), has catalyzed the development of numerous neutralizing therapeutic agents. The validity of VEGF inhibition as a therapeutic strategy has been well supported in randomized clinical trials, as well as U.S. Food and Drug Administration approval of the VEGF antagonists bevacizumab, sunitinib malate, sorafenib, pegaptinib and ranibizumab. Accordingly, this review will (1) briefly review the basic molecular biology of VEGF and (2) summarize recent progress in targeting the VEGF molecular pathway as therapy for angiogenic diseases such as cancer and age-related macular degeneration.