Inhibition of TNFR1 Attenuates LPS Induced Apoptosis and Inflammation in Human Nucleus Pulposus Cells by Regulating the NF-KB and MAPK Signalling Pathway

Neurochemical Research - Intervertebral disc degeneration (IDD) is accompanied by nucleus pulposus (NP) cell apoptosis, inflammation, and extracellular matrix degradation. Tumour necrosis factor...     

Topological evolution of coexpression networks by new gene integration maintains the hierarchical and modular structures in human ancestors

We analyze the global structure and evolution of human gene coexpression networks driven by new gene integration. When the Pearson correlation coefficient is greater than or equal to 0.5, we find that the coexpression network consists of 334 small components and one "giant" connected subnet comprising of 6317 interacting genes. This network shows the properties of power-law degree distribution and small-world. The average clustering coefficient of younger genes is larger than that of the elderly genes(0.6685 vs. 0.5762). Particularly, we find that the younger genes with a larger degree also show a property of hierarchical architecture. The younger genes play an important role in the overall pivotability of the network and this network contains few redundant duplicate genes. Moreover, we find that gene duplication and orphan genes are two dominant evolutionary forces in shaping this network. Both the duplicate genes and orphan genes develop new links through a "rich-gets-richer"mechanism. With the gradual integration of new genes into the ancestral network, most of the topological structure features of the network would gradually increase. However, the exponent of degree distribution and modularity coefficient of the whole network do not change significantly, which implies that the evolution of coexpression networks maintains the hierarchical and modular structures in human ancestors.     

MARCH2 regulates autophagy by promoting CFTR ubiquitination and degradation and PIK3CA-AKT-MTOR signaling

MARCH2 (membrane-associated RING-CH protein 2), an E3 ubiquitin ligase, is mainly associated with the vesicle trafficking. In the present study, for the first time, we demonstrated that MARCH2 negatively regulates autophagy. Our data indicated that overexpression of MARCH2 impaired autophagy, as evidenced by attenuated levels of LC3B-II and impaired degradation of endogenous and exogenous autophagic substrates. By contrast, loss of MARCH2 expression had the opposite effects. In vivo experiments demonstrate that MARCH2 knockout mediated autophagy results in an inhibition of tumorigenicity. Further investigation revealed that the induction of autophagy by MARCH2 deficiency was mediated through the PIK3CA-AKT-MTOR signaling pathway. Additionally, we found that MARCH2 interacts with CFTR (cystic fibrosis transmembrane conductance regulator), promotes the ubiquitination and degradation of CFTR, and inhibits CFTR-mediated autophagy in tumor cells. The functional PDZ domain of MARCH2 is required for the association with CFTR. Thus, our study identified a novel negative regulator of autophagy and suggested that the physical and functional connection between the MARCH2 and CFTR in different conditions will be elucidated in the further experiments.