Targeting stem cell signaling pathways for drug discovery:advances in the Notch and Wnt pathways

Signaling pathways transduce extracellular stimuli into cells through molecular cascades to regulate cellular functions.In stem cells,a small number of pathways,notably those of TGF-?/BMP,Hedgehog,Notch,and Wnt,are responsible for the regulation of pluripotency and differentiation.During embryonic development,these pathways govern cell fate specifications as well as the formation of tissues and organs.In adulthood,their normal functions are important for tissue homeostasis and regeneration,whereas aberrations result in diseases,such as cancer and degenerative disorders.In complex biological systems,stem cell signaling pathways work in concert as a network and exhibit crosstalk,such as the negative crosstalk between Wnt and Notch.Over the past decade,genetic and genomic studies have identified a number of potential drug targets that are involved in stem cell signaling pathways.Indeed,discovery of new targets and drugs for these pathways has become one of the most active areas in both the research community and pharmaceutical industry.Remarkable progress has been made and several promising drug candidates have entered into clinical trials.This review focuses on recent advances in the discovery of novel drugs which target the Notch and Wnt pathways.

Antiviral Drugs(Synthetic Small Molecule Inhibitors and Nature Drugs)Against EV71 in Enteroviruses:Advances and Perspectives

Background:Enterovirus 71(EV71)is a major virus that causes hand-foot-mouth disease.In cases of infants and young children,EV71 infection has been associated with severe neurological disease and potentially fatal systemic complications.The sporadic outbreak worldwide is increasingly prevalent in the Asia-Pacific region,where it has become a major public health concern.Objective:No specific antiviral drugs are currently approved for the treatment of EV71 infection.The purpose of this study is to comprehensively review the research progress of anti-EV71 drugs(synthetic small molecule inhibitors and nature drugs)in the past twenty years,and further to promote the research and development of antiviral drugs against enterovirus infection.Methods:This study reviewed the drugs on anti EV71 in the past decades.The literature search in PubMed database was conducted for original studies and review articles on drugs against enterovirus 71.Related articles published in English were selected for study and discussion.Results:As reviewed in this paper,bioactive molecules include receptor analogues,protease inhibitors,natural drugs derived from traditional chinese medicine or natural medicine.These bioactive molecules have shown significant effectiveness in inhibiting the entry and replication of EV71 in vitro and in vivo experiments.Conclusion:This review demonstrated that the entry receptor of EV71 into host cells has been studied,and receptor drugs against enterovirus have been made some progress,but most receptor analogues have not been reported.Further research is needed in this area in the future.On the other hand,the protease inhibitors have always been a major aspect of anti-enterovirus research and can be developed as antiviral agents for clinical application.In terms of natural drugs,many monomers derived from traditional chinese medicine or natural medicine have good antiviral activity and little toxic and side effects on host cells,but in view of their multi-target properties,the mechanism of drug action needs to be further studied.

Genome editing and animal models

Transgenic technology allows a gene of interest to be introduced into the genome of a laboratory animal,and provides an extremely powerful tool to dissect the molecular mechanisms of disease.Transgenic mouse models made by microinjection of DNA into zygotic pronuclei in particular have been widely used by the genetics community for 30 years.However,it remains a rather crude approach:injected sequences randomly insert in multiple copies as concatamers,they can be mutagenic,and they have variable or silenced expression depending on the site of integration,a phenomenon called position effects.As a result,multiple lines are required in order to confirm appropriate transgene expression.This can be partially overcome by flanking transgenes with insulator sequences to protect the transgene from the influence of the surrounding regulatory elements.Large(\300 kb)BACbased transgenic vectors have also been shown to be more resistant to position effects.However,animals carrying extra copies of fairly large regions of the genome could have unpredictable phenotypes.The most effective method used to control for position effects is to target transgene insertion to specific genomic loci,the so-called targeted transgenesis;for instance,the fast,site-specific transgenic technology Targatt TM.The purpose of this review is to provide an overview on the current existing methods for making targeted transgenic mouse models.

Intraneuronal accumulation of Aβ42 induces age-dependent slowing of neuronal transmission in Drosophila

Beta amyloid （Aβ42）-induced dysfunction and loss of synapses are believed to be major underlying mechanisms for the progressive loss of learning and memory abilities in Alzheimer＇s disease （AD）. The vast majority of investigations on AD-related synaptic impairment focus on synaptic plasticity, especially the decline of long-term potentiation of synaptic transmission caused by extracellular Aβ42. Changes in other aspects of synaptic and neuronal functions are less studied or undiscovered. Here, we report that intraneuronal accumulation of Aβ42 induced an age- dependent slowing of neuronal transmission along pathways involving multiple synapses.