ARID1A expression in intrahepatic cholangiocarcinoma and its relationship with tumor recurrence,metastasis and tumor-specific immunomarkers / 中华普通外科杂志

Objective:To investigate the expression level between AT-Rich Interaction Domain 1A(ARID1A) in intrahepatic cholangiocarcinoma (ICC) and the correlation with tumor microenvironment.Methods:The clinicopathological and survival data of 110 ICC patients undergoing radical hepatectomy in Peking University People's Hospital from Jan 2015 to May 2021 were retrospectively analyzed. Immunohistochemical staining was used to detect the expressions of ARID1A , programmed cell death 1 ligand 1( PD-L1) in tumor tissues , programmed cell death protein 1(PD-1) and cluster of differentiation 8(CD8) in the microenvironment. The relationship between ARID1A expression and PD-L1, PD-1, CD8 protein expression was analyzed.Results:Twenty seven patients did not express ARID1A, absence of ARID1A was associated with high PD-L1, PD-1 and CD8 expression ( P<0.05). Multivariate analysis showed ARID1A expression, preoperative CEA level,preoperative CA19-9 level, lymph node metastasis and tumor number were independent risk factors. Conclusion:Absent expression of ARID1A suggests poor prognosis of ICC patients, high expression of PD-L1,PD-1 and CD8 protein in ICC tumor microenvironment with ARID1A-deficient expression suggests a possible prognosis benefit by using anti-PD-1, anti-PD-L1 and other immunotherapy regimens.

Bioinformatics analysis of differentially expressed proteins in human lung adenocarcinoma / 中国医师杂志

Objective To investigate the biological significance of differentially expressed proteins from human primary lung adenocarcinoma with lymph node metastasis adenocarcinoma (LNM AdC) and without metastasis (non-LNM AdC) according to clinical diagnosis of lymph node metastasis and distant metastasis,with bioinformatics approach.Methods Cytoscape software was used to analyze a functional enrichment analysis and a protein-protein interaction network from differentially expressed proteins from LNM AdC and non-LNM AdC.Results The top biological processes were related to glucose catabolic process,hexose catabolic process,monosaccharide catabolic process,alcohol catabolic process,and cellular carbohydrate catabolic process.The top molecular functions were related to phospholipase inhibitor activity,lipase inhibitor activity,calcium-dependent phospholipid binding,phosphlipase A2 inhibitor activity,and lipid binding.A protein-protein interaction network of differentially expressed proteins was generated with literature data.Conclusions This bioinformatics analysis demonstrated that glucose catabolic process,alcohol catabolic process,calcium-dependent phospholipid binding,phosphlipase A2 inhibitor activity,ACTB,ANXA1,ANXA2,ANXA3,VCP,NPM1,KRT1,and SUMO4 are significantly associated with a lung adenocarcinoma.These network data provide new insights into the metastasis mechanisms of human lung adenocarcinoma.

Homophilic interaction of the L1 family of cell adhesion molecules

Homophilic interaction of the L1 family of cell adhesion molecules plays a pivotal role in regulating neurite outgrowth and neural cell networking in vivo. Functional defects in L1 family members are associated with neurological disorders such as X-linked mental retardation, multiple sclerosis, low-IQ syndrome, developmental delay, and schizophrenia. Various human tumors with poor prognosis also implicate the role of L1, a representative member of the L1 family of cell adhesion molecules, and ectopic expression of L1 in fibroblastic cells induces metastasis-associated gene expression. Previous studies on L1 homologs indicated that four N-terminal immunoglobulin-like domains form a horseshoe-like structure that mediates homophilic interactions. Various models including the zipper, domain-swap, and symmetry-related models are proposed to be involved in structural mechanism of homophilic interaction of the L1 family members. Recently, cryo-electron tomography of L1 and crystal structure studies of neurofascin, an L1 family protein, have been performed. This review focuses on recent discoveries of different models and describes the possible structural mechanisms of homophilic interactions of L1 family members. Understanding structural mechanisms of homophilic interactions in various cell adhesion proteins should aid the development of therapeutic strategies for L1 family cell adhesion molecule-associated diseases.

Intracellular amyloid beta interacts with SOD1 and impairs the enzymatic activity of SOD1: implications for the pathogenesis of amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease caused by the degeneration of motor neurons. Mutations in Cu/Zn superoxide dismutase (SOD1), including G93A, were reportedly linked to familial ALS. SOD1 is a key antioxidant enzyme, and is also one of the major targets for oxidative damage in the brains of patients suffering from Alzheimer's disease (AD). Several lines of evidence suggest that intracellular amyloid beta (Abeta) is associated with the pathogenesis of AD. In this report we demonstrate that intracellular Abeta directly interacts with SOD1, and that this interaction decreases the enzymatic activity of the enzyme. We observed Abeta-SOD1 aggregates in the perinuclear region of H4 cells, and mapped the SOD1 binding region to Abeta amino acids 26-42. Interestingly, intracellular Abeta binds to the SOD1 G93A mutant with greater affinity than to wild-type SOD1. This resulted in considerably less mutant enzymatic activity. Our study implicates a potential role for Abeta in the development of ALS by interacting with the SOD1 G93A mutant.

Ubiquitylation of Fe65 adaptor protein by neuronal precursor cell expressed developmentally down regulated 4-2 (Nedd4-2) via the WW domain interaction with Fe65

Fe65 has been characterized as an adaptor protein, originally identified as an expressed sequence tag (EST) corresponding to an mRNA expressed at high levels in the rat brain. It contains one WW domain and two phosphotyrosine interaction/phosphotyrosine binding domains (PID1/PID2). As the neuronal precursor cell expressed developmentally down regulated 4-2 (Nedd4-2) has a putative WW domain binding motif (72PPLP75) in the N-terminal domain, we hypothesized that Fe65 associates with Nedd4-2 through a WW domain interaction, which has the characteristics of E3 ubiquitin-protein ligase. In this paper, we present evidence for the interaction between Fe65 WW domain and Nedd4-2 through its specific motif, using a pull down approach and co-immunoprecipitation. Additionally, the co-localization of Fe65 and Nedd4-2 were observed via confocal microscopy. Co-localization of Fe65 and Nedd4-2 was disrupted by either the mutation of Fe65 WW domain or its putative binding motif of Nedd4-2. When the ubiquitin assay was performed, the interaction of Nedd4-2 (wt) with Fe65 is required for the cell apoptosis and the ubiquitylation of Fe65. We also observed that the ubiquitylation of Fe65 (wt) was augmented depending on Nedd4-2 expression levels, whereas the Fe65 WW domain mutant (W243KP245K) or the Nedd4-2 AL mutant (72PPLP75 was changed to 72APLA75) was under-ubiquitinated significantly. Thus, our observations implicated that the protein-protein interaction between the WW domain of Fe65 and the putative binding motif of Nedd4-2 down-regulates Fe65 protein stability and subcellular localization through its ubiquitylation, to contribute cell apoptosis.

Interaction of δ-opioid Receptor with Membrane Transporters: Possible Mechanisms in Pain Suppression by Acupuncture / 针灸推拿医学（英文版）

Objective: To investigate the possible mechanisms in acupuncture analgesia by interaction of &opioid receptor with neurotransmitter transport proteins or the Na+-K+pump. Methods: Microinjection of respective heterologous cRNA into the Xenopus oocytes as a model system, and measurement of steady-state currents under two-electrode voltage clamp. Results: The co-expression of the δ-opioid receptor with GAT1, EAAC1 or the sodium pump resulted in reducing activity of the respective transporter. Opioid receptor activation affected transporter activity in different ways: 1) GAT1 was further inhibited; 2) EAAC1 was stimulated; 3) Na+-K+ pump activity interfered with agonist sensitivity of DOR. Pump inhibition led to higher sensitivity for DPDPE. Conclusion: GABA transporter inhibition and glutamate transporter stimulation may counteract pain sensation by affecting the neurotransmitter concentration in the synaptic cleft and, therefore, may contribute synergistically to pain suppression by acupuncture. Sodium pump inhibition by endogenous ouabain may amplify these effects. These synergistic effects may be the molecular mechanism of inhibiting pain sense and/or acupuncture analgesia.