Exosomes: the key of sophisticated cell–cell communication and targeted metastasis in pancreatic cancer

Pancreatic cancer is one of the most common malignancies. Unfortunately, the lack of effective methods of treatment and diagnosis has led to poor prognosis coupled with a very high mortality rate. So far, the pathogenesis and progression mechanisms of pancreatic cancer have been poorly characterized. Exosomes are small vesicles secreted by most cells, contain lipids, proteins, and nucleic acids, and are involved in diverse functions such as intercellular communications, biological processes, and cell signaling. In pancreatic cancer, exosomes are enriched with multiple signaling molecules that mediate intercellular communication with control of immune suppression, mutual promotion between pancreas stellate cells and pancreatic cancer cells, and reprogramming of normal cells. In addition, exosomes can regulate the pancreatic cancer microenvironment and promote the growth and survival of pancreatic cancer. Exosomes can also build pre-metastatic micro-ecological niches and facilitate the targeting of pancreatic cancer. The ability of exosomes to load cargo and target allows them to be of great clinical value as a biomarker mediator for targeted drugs in pancreatic cancer.

Shp2 in uterine stromal cells critically regulates on time embryo implantation and stromal decidualization by multiple pathways during early pregnancy

Approximately 75% of failed pregnancies are considered to be due to embryo implantation failure or defects. Nevertheless, the explicit signaling mechanisms governing this process have not yet been elucidated. Here, we found that conditional deletion of the Shp2 gene in mouse uterine stromal cells deferred embryo implantation and inhibited the decidualization of stromal cells, which led to embryonic developmental delay and to the death of numerous embryos mid-gestation, ultimately reducing female fertility. The absence of Shp2 in stromal cells increased the proliferation of endometrial epithelial cells, thereby disturbing endometrial epithelial remodeling. However, Shp2 deletion impaired the proliferation and polyploidization of stromal cells, which are distinct characteristics of decidualization. In human endometrial stromal cells (hESCs), Shp2 expression gradually increased during the decidualization process. Knockout of Shp2 blocked the decidual differentiation of hESCs, while Shp2 overexpression had the opposite effect. Shp2 knockout inhibited the proliferation of hESCs during decidualization. Whole gene expression profiling analysis of hESCs during the decidualization process showed that Shp2 deficiency disrupted many signaling transduction pathways and gene expression. Analyses of hESCs and mouse uterine tissues confirmed that the signaling pathways extracellular regulated protein kinases (ERK), protein kinase B (AKT), signal transducer and activator of transcription 3 (STAT3) and their downstream transcription factors CCAAT/enhancer binding protein β (C/EBPβ) and Forkhead box transcription factor O1 (FOXO-1) were involved in the Shp2 regulation of decidualization. In summary, these results demonstrate that Shp2 plays a crucial role in stromal decidualization by mediating and coordinating multiple signaling pathways in uterine stromal cells. Our discovery possibly provides a novel key regulator of embryo implantation and novel therapeutic target for pregnancy failure.

Fine-Tuning of the Grain Size by Alternative Splicing of GS3 in Rice

Grain size is subtly regulated by multiple signaling pathways in rice. Alternative splicing is a general mechanism that regulates gene expression at the post-transcriptional level. However, to our knowledge, the molecular mechanism underlying grain size regulation by alternative splicing is largely unknown. GS3, the first identified QTL for grain size in rice, is regulated at the transcriptional and post-translational level. In this study, we identified that GS3 is subject to alternative splicing. GS3.1 and GS3.2, two dominant isoforms, accounts for about 50% and 40% of total transcripts, respectively. GS3.1 encodes the full-length protein, while GS3.2 generated a truncated proteins only containing OSR domain due to a 14 bp intronic sequence retention. Genetic analysis revealed that GS3.1 overexpressors decreased grain size, but GS3.2 showed no significant effect on grain size. Furthermore, we demonstrated that GS3.2 disrupts GS3.1 signaling by competitive occupation of RGB1. Therefore, we draw a conclusion that the alternative splicing of GS3 decreases the amount of GS3.1 and GS3.2 disrupts the GS3.1 signaling to inhibit the negative effects of GS3.1 to fine-tune grain size. Moreover, the mechanism is conserved in cereals rather than in Cruciferae, which is associated with its effects on grain size. The results provide a novel, conserved and important mechanism underlying grain size regulation at the post-transcriptional level in cereals.

Extracellular ATP plays an important role in systemic wound response activation

Mechanical wounding occurs in plants during biotic (e.g., herbivore or pathogen attack) or abiotic (e.g., wind damage or freezing) stresses and is associated with the activation of multiple signaling pathways. These initiate many wound responses at the wounded tissues, as well as trigger long-distance signaling pathways that activate wound responses in tissues that were not affected by the initial wounding event (termed systemic wound response). Among the different systemic signals activated by wounding are electric signals, calcium and reactive oxygen species (ROS) waves, and different plant hormones such as jasmonic acid. The release of glutamate from cells at the wounded tissues was recently proposed to trigger several different systemic signal transduction pathways via glutamate-like receptors (GLRs). However, the role of another important compound released from cells during wounding (i.e., extracellular ATP; eATP) in triggering systemic responses is not clear. Here we show that eATP that accumulates in wounded leaves and is sensed by the purinoreceptor kinase P2K is required for the activation of the ROS wave during wounding. Application of eATP to unwounded leaves triggered the ROS wave, and the activation of the ROS wave by wounding or eATP application was suppressed in mutants deficient in P2K (i.e., p2k1-3, p2k2, and p2k1-3p2k2). In addition, the expression of several systemic wound response transcripts was suppressed in mutants deficient in P2K during wounding. Our findings reveal that in addition to sensing glutamate via GLRs, eATP sensed by P2Ks is playing a key role in the triggering of systemic wound responses in plants.

Editorial – Disc Biology Special Issue

The intervertebral disc (IVD) has long been known as a mechanical structure responsible for spinal flexibility and load distribution, while its dysfunction is a frequent source of pain and disability. In recent years, multiple signaling pathways contributing to the regulation of the IVD homeostasis in health and disease have been discovered. At the same time, crosstalk of the IVD with adjacent tissues, immune cells, nerve cells and systemic mediators has been identified as an essential mechanism of degeneration and repair. Such discoveries open the door for the design of new therapeutic and diagnostic targets. This Disc Biology Special Issue provides an abstract of cutting-edge findings in terms of tissue regulation, therapeutic intervention and preclinical models, which will help to improve the management of IVD disorders.

EGF-induced nuclear translocation of SHCBP1 promotes bladder cancer progression through inhibiting RACGAP1-mediated RAC1 inactivation

Bladder cancer is a highly heterogeneous and aggressive malignancy with a poor prognosis. EGF/EGFR activation causes the detachment of SHC-binding protein 1 (SHCBP1) from SHC adapter protein 1 (SHC1), which subsequently translocates into the nucleus and promotes cancer development via multiple signaling pathways. However, the role of the EGF-SHCBP1 axis in bladder cancer progression remains unexplored. Herein, we report that SHCBP1 is upregulated in bladder cancer tissues and cells, with cytoplasmic or nuclear localization. Released SHCBP1 responds to EGF stimulation by translocating into the nucleus following Ser273 phosphorylation. Depletion of SHCBP1 reduces EGF-induced cell migration and invasiveness of bladder cancer cells. Mechanistically, SHCBP1 binds to RACGAP1 via its N-terminal domain of amino acids 1 ~ 428, and this interaction is enhanced following EGF treatment. Furthermore, SHCBP1 facilitates cell migration by inhibiting RACGAP-mediated GTP-RAC1 inactivation, whose activity is indispensable for cell movement. Collectively, we demonstrate that the EGF-SHCBP1-RACGAP1-RAC1 axis acts as a novel regulatory mechanism of bladder cancer progression, which offers a new clinical therapeutic strategy to combat bladder cancer.

Automatic Activity Arising in Cardiac Muscle Sleeves of the Pulmonary Vein

Ectopic activity in the pulmonary vein cardiac muscle sleeves can both induce and maintain human atrial fibrillation. A central issue in any study of the pulmonary veins is their difference from the left atrial cardiac muscle. Here, we attempt to summarize the physiological phenomena underlying the occurrence of ectopic electrical activity in animal pulmonary veins. We emphasize that the activation of multiple signaling pathways influencing not only myocyte electrophysiology but also the means of excitation–contraction coupling may be required for the initiation of triggered or automatic activity. We also gather information regarding not only the large-scale structure of cardiac muscle sleeves but also recent studies suggesting that cellular heterogeneity may contribute to the generation of arrythmogenic phenomena and to the distinction between pulmonary vein and left atrial heart muscle.

Role of Fyn Kinase Inhibitors in Switching Neuroinflammatory Pathways

Fyn kinase is a member of the Src non-receptor tyrosine kinase family. Fyn is involved in multiple signaling pathways extending from cell proliferation and differentiation to cell adhesion and cell motility, and it has been found to be overexpressed in various types of cancers. In the central nervous system, Fyn exerts several different functions such as axon–glial signal transduction, oligodendrocyte maturation and myelination, and it is implicated in neuroinflammatory processes. Based on these premises, Fyn emerges as an attractive target in cancer and neurodegenerative disease therapy, particularly Alzheimer disease (AD), based on its activation by Aβ via cellular prion protein and its interaction with tau protein. However, Fyn is also a challenging target since the Fyn inhibitors discovered so far, due to the relevant homology of Fyn with other kinases, suffer from off-target effects. This review covers the efforts performed in the last decade to identify and optimize small molecules that effectively inhibit Fyn, both in enzymatic and in cell assays, including drug repositioning practices, as an opportunity of therapeutic intervention in neurodegeneration.

Prediction of the anti-inflammatory effects of bioactive components of a Hippocampus species-based TCM formulation on chronic kidney disease using network pharmacology

Purpose: To systematically study and predict the therapeutic targets and signaling pathways of Hippocampus (HPC) against chronic kidney disease (CKD) using network pharmacology.Methods: By combining database mining, literature searching, screening of disease targets, and network construction, the effects of various components of HPC on several proteins related to CKD were predicted and the active compounds were screened. Genes related to the selected compounds were linked using the SEA database. The correlation between CKD and genes was determined using OMIM, DisGenNet, and GeneCards databases. Pathway-enrichment analyses of overlapping genes were undertaken using online databases.Results: A total of 144 compounds in HPC were identified. Analyses of clusters suggest that the active components of HPC and the target genes against the inflammation caused by CKD were due to 10 compounds and 25 genes. Metascape results showed that these HPC targets are related to CKD inflammation.Conclusion: The active components of HPC and the target genes against CKD inflammation are involved in multiple signaling pathways, such as AGE-RAGE, TLR, TNF, and NF-κB. This work provides scientific evidence to support the clinical use of HPC against CKD.