Molecular mechanisms of NMDA receptor-mediated excitotoxicity:implications for neuroprotective therapeutics for stroke

Excitotoxicity is a process observed in many disease states by which an excessive synaptic excitation causes neuronal death, and is thought to be triggered by the extracellular accumulation of the excitatory neurotransmitter glutamate, which binds and activates ionotropic N-methyl-D-aspartate glutamatergic receptors （NMDARs） in the brain. Normally, NMDARs mediate calcium entry into the cell to regulate physiological processes such as synaptic plasticity and memory,

A Numerical Study of Passive Receptor-Mediated Endocytosis of Nanoparticles:The Effect of Mechanical Properties

In this work,a three-dimensional axisymmetric model with nanoparticle,receptor-ligand bonds and cell membrane as a system was used to study the quasi-static receptor-mediated endocytosis process of spherical nanoparticles in drug delivery.The minimization of the system energy function was carried out numerically,and the deformations of nanoparticle,receptor-ligand bonds and cell membrane were predicted.Results show that passive endocytosis may fail due to the rupture of receptor-ligand bonds during the wrapping process,and the size and rigidity of nanoparticles affect the total deformation energy and the terminal wrapping stage.Our results suggest that,in addition to the energy requirement,the success of passive endocytosis also depends on the maximum strength of the receptor-ligand bonds.

Receptor-mediated increase in rabies virus axonal transport

Rabies virus （RABV） of the rhabdoviridae family is a prototype neurotropic virus that causes a fatal disease, and is still a major risk mostly in developing countries. A key step in the RABV infection process is its arrival into the central nervous system （CNS）, for which it uses the cellular transport machinery. Neurons are irregular cells with a specialized anatomy, and often extend lengthy axons that may span over a meter long. In infected organisms, RABV virions enter the neuron periphery at the area of a bite and must overcome great distances in order to reach the peripheral neuron＇s cell body and from there,

Receptor-mediated targeted drug delivery systems for treatment of inflammatory bowel disease: Opportunities and emerging strategies

Inflammatory bowel disease(IBD)is a chronic intestinal disease with painful clinical manifestations and high risks of cancerization.With no curative therapy for IBD at present,the development of effective therapeutics is highly advocated.Drug delivery systems have been extensively studied to transmit therapeutics to inflamed colon sites through the enhanced permeability and retention(EPR)effect caused by the inflammation.However,the drug still could not achieve effective concentration value that merely utilized on EPR effect and display better therapeutic efficacy in the inflamed region because of nontargeted drug release.Substantial researches have shown that some specific receptors and cell adhesion molecules highly expresses on the surface of colonic endothelial and/or immune cells when IBD occurs,ligandmodified drug delivery systems targeting such receptors and cell adhesion molecules can specifically deliver drug into inflamed sites and obtain great curative effects.This review introduces the overexpressed receptors and cell adhesion molecules in inflamed colon sites and retrospects the drug delivery systems functionalized by related ligands.Finally,challenges and future directions in this field are presented to advance the development of the receptor-mediated targeted drug delivery systems for the therapy of IBD.

The crossroads of receptor-mediated signaling and endocytosis in plants

Plants deploy numerous plasma membrane receptors to sense and rapidly react to environmental changes. Correct localization and adequate protein levels of the cell-surface receptors are critical for signaling activation and modulation of plant development and defense against pathogens. After ligand binding, receptors are internalized for degradation and signaling attenuation. However, one emerging notion is that the Iigand-induced endocytosis of reCeptor complexes is important for the signal duration, amplitude, and specificity. Recently, mutants of maior endocytosis players, including clathrin and dynamin, have been shown to display defects in activation of a subset of signal transduction pathways, implying that signaling in plants might not be solely restricted to the plasma membrane. Here, we summarize the up-to-date knowledge of receptor complex endocytosis and its effect on the signaling outcome, in the context of plant development and immunity.

Di-PEGylated insulin:A long-acting insulin conjugate with superior safety in reducing hypoglycemic events

Although the discovery of insulin 100 years ago revolutionized the treatment of diabetes,its therapeutic potential is compromised by its short half-life and narrow therapeutic index.Current long-acting insulin analogs,such as insulin-polymer conjugates,are mainly used to improve pharmacokinetics by reducing renal clearance.However,these conjugates are synthesized without sacrificing the bioactivity of insulin,thus retaining the narrow therapeutic index of native insulin,and exceeding the efficacious dose still leads to hypoglycemia.Here,we report a kind of di-PEGylated insulin that can simultaneously reduce renal clearance and receptor-mediated clearance.By impairing the binding affinity to the receptor and the activation of the receptor,di-PEGylated insulin not only further prolongs the half-life of insulin compared to classical mono-PEGylated insulin but most importantly,increases its maximum tolerated dose 10-fold.The target of long-term glycemic management in vivo has been achieved through improved pharmacokinetics and a high dose.This work represents an essential step towards long-acting insulin medication with superior safety in reducing hypoglycemic events.

A novel receptor-targeted gene delivery system for cancer gene therapy

Some growth factor receptors, such as insulin like growth factor I and II receptor (IGF I R, IGF II R) and epidermal growth factor receptor (EGF R), have been proved to be over-expressed in a variety of human cancers derived from different tissue origins. Based on this molecular alteration, a polypeptide conjugate gene delivery system was designed and synthesized. It contains three essential moieties: a ligand oligopeptide (LOP) for receptor recognition, a polycationic polypeptide (PCP) such as protamine (PA) or poly-L-lysine (PL) as a backbone for DNA binding and an endosome-releasing oligopeptide (EROP) such as influenza haemagglutinin oligopeptide (HA20) for endosomol-ysis. These components are covalently conjugated as LOP-PCP-HA20 or in the form of a mixture of LOP-PCP and HA20-PCP. A 14 amino acid E5 was designed and synthesized as LOP for IGF I R and IGF II R, and a 16 amino acid GE7 as LOP for EGF R. Both E5 and GE7 systems could form stable complex with the plasmid DNA as E5-PCP/ DNA/PCP-HA20 and GE7-PCP/DNA/PCP-HA20. Using bacterial β-galactosidase gene (pSVβ-gal) as a reporter, the present system is able to efficiently target exogenous gene to human cancer cells of different tissue types with high efficiency both in vitro and in implanted tumors in nude mice. It was also demonstrated that the transduced genes were highly expressed in cancer cells both in vitro and in vivo . The present system will provide a novel effective vehicle to target therapeutic genes into cancer cells in gene therapy.

Asialoglycoprotein receptor and liposome synergistically mediate the gene transfer into primary rat hepatocytes

Gene transfer into primary rat hepatocytes was performed by employing cationic liposome as DNA carrier and the specific ligand of hepatic asialoglycoprotein receptor (ASGPR), asialofetuin, as liver-targeting ligand. The results showed that asialofetuin, when added to the gene transfer complexes, could significantly increase the hepatocyte transfection efficiency, and alleviate the cellular toxicity of Lipofectin. Several synthetic ligands of ASGPR (galactosyl albumin) could also increase the transfection efficiency of hepatocyte like asialofetuin. It was proved that ASGPR and cationic liposome could synergistically mediate the gene transfer into primary rat hepatocytes. This novel gene delivery system provided a safer, more simple and efficient gene transfer method for primary hepatocytes, and showed prospecting application in hepatic gene therapy.

Orange-derived extracellular vesicles nanodrugs for efficient treatment of ovarian cancer assisted by transcytosis effect

Extracellular vesicles(EVs)have recently received much attention about the application of drug carriers due to their desirable properties such as nano-size,biocompatibility,and high stability.Herein,we demonstrate orange-derived extracellular vesicles(OEV)nanodrugs(DN@OEV)by modifying cRGD-targeted doxorubicin(DOX)nanoparticles(DN)onto the surface of OEV,enabling significantly enhancing tumor accumulation and penetration,thereby efficiently inhibiting the growth of ovarian cancer.The obtained DN@OEV enabled to inducement of greater transcytosis capability in ovarian cancer cells,which presented the average above 10-fold transcytosis effect compared with individual DN.It was found that DN@OEV could trigger receptor-mediated endocytosis to promote early endosome/recycling endosomes pathway for exocytosis and simultaneously reduce degradation in the early endosomes-late endosomes-lysosome pathway,thereby inducing the enhanced transcytosis.In particular,the zombie mouse model bearing orthotopic ovarian cancer further validated DN@OEV presented high accumulation and penetration in tumor tissue by the transcytosis process.Our study indicated the strategy in enhancing transcytosis has significant implications for improving the therapeutic efficacy of thedrugdelivery system.