Exosomes are small membrane vesicles (ranging from 30 nm to 150 nm), secreted by different cell types upon fusion of multivesicular bodies (MVB) to the cell plasma membrane under a variety of normal ...and pathological conditions. Through transferring their cargos such as proteins, lipids and nucleic acids from donor cells to recipient cells, exosomes play a crucial role in cell-to-cell communication. Due to their presence in most body fluids (such as blood, breast milk, saliva, urine, bile, pancreatic juice, cerebrospinal and peritoneal fluids), and their role in carrying bioactive molecules from the cells of origin, exosomes have attracted great interest in their diagnostic and prognostic value for various diseases and therapeutic approaches. Although a large body of literature has documented the importance of exosomes over the past decade, there is no article systematically summarizing protein markers of exosome from different resources and the antibodies that are suited to characterize exosomes. In this review, we briefly summarize the exosome marker proteins, exosomal biomarkers for different diseases, and the antibodies suitable for different bio-resources exosomes characterization.
Increased hepatic ischemia-reperfusion (IR) injury in steatotic livers is a major reason for rejecting the use of fatty livers for liver transplantation. Necroptosis is implicated in the pathogenesis ...of fatty liver diseases. Necroptosis is regulated by three key proteins: receptor-interacting serine/threonine-protein kinase (RIPK)-1, RIPK3, and mixed-lineage kinase domain–like protein (MLKL). Here, we found that marked steatosis of the liver was induced when a Western diet was given in mice; steatosis was associated with the inhibition of hepatic proteasome activities and with increased levels of key necroptosis-related proteins. Mice fed a Western diet had more severe liver injury, as demonstrated by increases in serum alanine aminotransferase and necrotic areas of liver, after IR than did mice fed a control diet. Although hepatic steatosis was not different between Mlkl knockout mice and wild-type mice, Mlkl knockout mice had decreased hepatic neutrophil infiltration and inflammation and were protected from hepatic IR injury, irrespective of diet. Intriguingly, Ripk3 knockout or Ripk3 kinase-dead knock-in mice were protected against IR injury at the late phase but not the early phase, irrespective of diet. Overall, our findings indicate that liver steatosis exacerbates hepatic IR injury via increased MLKL-mediated necroptosis. Targeting MLKL-mediated necroptosis may help to improve outcomes in steatotic liver transplantation.
Autophagy is a lysosomal degradation pathway that degrades cytoplasmic proteins and organelles. Absence of autophagy in hepatocytes has been linked to promoting liver injury and tumorigenesis; ...however, the mechanisms behind why a lack of autophagy induces these complications are not fully understood. The role of mammalian target of rapamycin (mTOR) in impaired autophagy‐induced liver pathogenesis and tumorigenesis was investigated by using liver‐specific autophagy related 5 knockout (L‐ATG5 KO) mice, L‐ATG5/mTOR, and L‐ATG5/Raptor double knockout (DKO) mice. We found that deletion of mTOR or Raptor in L‐ATG5 KO mice at 2 months of age attenuated hepatomegaly, cell death, and inflammation but not fibrosis. Surprisingly, at 6 months of age, L‐ATG5/mTOR DKO and L‐ATG5/Raptor DKO mice also had increased hepatic inflammation, fibrosis, and liver injury, similar to the L‐ATG5 KO mice. Moreover, more than 50% of L‐ATG5/mTOR DKO and L‐ATG5/Raptor DKO mice already developed spontaneous tumors, but none of the L‐ATG5 KO mice had developed any tumors at 6 months of age. At 9 months of age, all L‐ATG5/mTOR DKO and L‐ATG5/Raptor DKO had developed liver tumors. Mechanistically, L‐ATG5/mTOR DKO and L‐ATG5/Raptor DKO mice had decreased levels of hepatic ubiquitinated proteins and persistent nuclear erythroid 2 p45‐related factor 2 activation but had increased Akt activation compared with L‐ATG5 KO mice. Conclusion: Loss of mTOR signaling attenuates the liver pathogenesis in mice with impaired hepatic autophagy but paradoxically promotes tumorigenesis in mice at a relatively young age. Therefore, the balance of mTOR is critical in regulating the liver pathogenesis and tumorigenesis in mice with impaired hepatic autophagy.
Oomycete pathogens cause serious damage to a wide spectrum of plants. Although host pathogen recognition via pathogen effectors and cognate plant resistance proteins is well established, the genetic ...basis of host factors that mediate plant susceptibility to oomycete pathogens is relatively unexplored. Here, we report on RTP1, a nodulin‐related MtN21 family gene in Arabidopsis that mediates susceptibility to Phytophthora parasitica. RTP1 was identified by screening a T‐DNA insertion mutant population and encoded an endoplasmic reticulum (ER)‐localized protein. Overexpression of RTP1 rendered Arabidopsis more susceptible, whereas RNA silencing of RTP1 led to enhanced resistance to P. parasitica. Moreover, an RTP1 mutant, rtp1‐1, displayed localized cell death, increased reactive oxygen species (ROS) production and accelerated PR1 expression, compared to the wild‐type Col‐0, in response to P. parasitica infection. rtp1‐1 showed a similar disease response to the bacterial pathogen Pseudomonas syringae pv. tomato (Pst) DC3000, including increased disease resistance, cell death and ROS production. Furthermore, rpt1‐1 exhibited resistance to the fungal pathogen Golovinomyces cichoracearum, but not to the necrotrophic pathogen Botrytis cinerea. Taken together, these results suggest that RTP1 negatively regulates plant resistance to biotrophic pathogens, possibly by regulating ROS production, cell death progression and PR1 expression.
Plants are continually exposed to a variety of pathogenic organisms, including bacteria, fungi and viruses. In response to these assaults, plants have developed various defense pathways to protect ...themselves from pathogen invasion. An understanding of the expression and regulation of genes involved in defense signaling is essential to controlling plant disease. ATL9, an Arabidopsis RING zinc finger protein, is an E3 ubiquitin ligase that is induced by chitin and involved in basal resistance to the biotrophic fungal pathogen, Golovinomyces cichoracearum (G. cichoracearum). To better understand the expression and regulation of ATL9, we studied its expression pattern and the functions of its different protein domains. Using pATL9:GUS transgenic Arabidopsis lines we found that ATL9 is expressed in numerous tissues at various developmental stages and that GUS activity was induced rapidly upon wounding. Using a GFP control protein, we showed that ATL9 is a short-lived protein within plant cells and it is degraded via the ubiquitin-proteasome pathway. ATL9 contains two transmembrane domains (TM), a RING zinc-finger domain, and a PEST domain. Using a series of deletion mutants, we found that the PEST domain and the RING domain have effects on ATL9 degradation. Further infection assays with G. cichoracearum showed that both the RING domain and the TM domains are important for ATL9's resistance phenotype. Interestingly, the PEST domain was also shown to be significant for resistance to fungal pathogens. This study demonstrates that the PEST domain is directly coupled to plant defense regulation and the importance of protein degradation in plant immunity.
Cell-to-cell communication is a fascinating process that is essential for maintaining tissue and whole-body homeostasis. Extracellular vesicles (EVs) are cell-derived membrane-bound nanoparticles ...that are a means of communication between cells. Accumulating evidence indicates that EVs can render either beneficial or harmful outcomes, depending on the specific cargos (e.g., proteins, lipids, RNAs) transferred between cells. EVs also have great value as diagnostic and prognostic markers of disease because they are present in a variety of biological fluids and carry bioactive molecules from their cells or tissues of origin. Liver cells can both release and receive EVs derived from other cells and emerging evidence indicates that liver EVs play important roles in the pathogenesis of various liver diseases, including liver cancer, viral hepatitis, non-alcoholic fatty liver disease, and alcoholic liver disease. This review provides an overview of the biogenesis and secretion of EVs and summarizes the most recent advances in understanding the role of EVs in liver physiology and diseases. Additionally, we discuss potential applications of liver EVs as biomarkers and in therapeutic approaches to treat liver diseases.
For the past several years, modal controllers are widely studied and used in the field of vibration or vibro-acoustics control. They are efficient but not robust, because these methods involve a ...reconstructor based on a modal truncation. When the dynamic behavior of the structure change, the controller and reconstructor must be updated to cope with the changes in the structure behavior, in order to maintain both performance and robustness. A solution is adaptive control but this approach needs some specific information not generally available particularly in the case of undergone modifications. This paper deals with a self-adaptive modal control based on a real-time identifier, which avoid the need of specific information. The identifier permits to update the controller and the reconstructor according to the changes of modal characteristics of time-varying structures. A classical algorithm of identification is used to obtain a state space model with an unspecified state vector. Then, based on this model, a well adapted transformation is carried out to get the modal characteristics from the expression of complex modes, including the mode shapes. As a criterion of running identification, the value of “variance-accounted for” (VAF) is employed to carry out the identifier only when the initial or previous model is not enough exact. A Linear Quadratic Gaussian Algorithm is employed in such a way that the controller and observer can be optimized according to the updated modal model. By this way, a self-adaptive modal control is completed and can demonstrate some smart properties. The proposed methodology is carried out on a simple but representative time-varying mechanical discrete structure. An inertia modification leads not only to low modal frequency shifts but also to inversion of a mode shape which is shown to lead to unstable configuration when control system is not updated. The overall procedure will be described through simulations and performed for different operating conditions, which will prove that mode shapes have to be precisely determined and updated in the controller and observer to guarantee a robust modal control with high performance in spite of the changes of structure.
Nonalcoholic fatty liver disease (NAFLD) is a burgeoning health problem worldwide, ranging from nonalcoholic fatty liver (NAFL, steatosis without hepatocellular injury) to the more aggressive ...nonalcoholic steatohepatitis (NASH, steatosis with ballooning, inflammation, or fibrosis). Although many studies have greatly contributed to the elucidation of NAFLD pathogenesis, the disease progression from NAFL to NASH remains incompletely understood. Nuclear receptor small heterodimer partner (Nr0b2, SHP) is a transcriptional regulator critical for the regulation of bile acid, glucose, and lipid metabolism. Here, we show that SHP levels are decreased in the livers of patients with NASH and in diet-induced mouse NASH. Exposing primary mouse hepatocytes to palmitic acid and lipopolysaccharide in vitro, we demonstrated that the suppression of Shp expression in hepatocytes is due to c-Jun N-terminal kinase (JNK) activation, which stimulates c-Jun–mediated transcriptional repression of Shp. Interestingly, in vivo induction of hepatocyte-specific SHP in steatotic mouse liver ameliorated NASH progression by attenuating liver inflammation and fibrosis, but not steatosis. Moreover, a key mechanism linking the anti-inflammatory role of hepatocyte-specific SHP expression to inflammation involved SHP-induced suppression of NF-κB p65-mediated induction of chemokine (C–C motif) ligand 2 (CCL2), which activates macrophage proinflammatory polarization and migration. In summary, our results indicate that a JNK/SHP/NF-κB/CCL2 regulatory network controls communications between hepatocytes and macrophages and contributes to the disease progression from NAFL to NASH. Our findings may benefit the development of new management or prevention strategies for NASH.
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