EFFECTS OF BRAIN-DERIVED NEUROTROPHIC FACTOR AND ITS SIGNALING PATHWAY ON SENSORY NEURONAL ACTIVATION DURING COLITIS

Visceral hypersensitivity is the heightened response to sensory stimuli. Visceral sensations are transmitted through primary afferent neurons in the dorsal root ganglion (DRG) and the sensitization of the neural pathway leads to modification in spinal ascending and descending neurons. The aim of this investigation is to determine the effects of brain-derived neurotrophic factor (BDNF) and its signaling pathway on sensory neuronal activation during colitis. In order to evaluate this, levels of calcitonin-gene related peptide (CGRP), a neuropeptide marker for nociceptive transmission, and phosphorylated cAMP-response element binding protein (pCREB), a molecular switch in neuronal plasticity, were studied in response to BDNF in vivo and in vitro. Colitis caused an increase in the levels of CGRP and pCREB in thoracolumbar DRG, which was attenuated by BDNF neutralizing antibody and PLC inhibitor, U73122, but not PI3K inhibitor, LY294002. BDNF-induced CGRP expression and CREB activation in DRG culture was also blocked by PLC inhibitor, U73122, but not PI3K inhibitor, LY294002, or MEK kinase inhibitor, PD98059. These results suggest a unique signaling pathway, i.e. the PLC-γ pathway, is mediating BDNF action on sensory neuronal activation during colitis

Impact of V-ets Erythroblastosis Virus E26 Oncogene Homolog 1 Gene Polymorphisms Upon Susceptibility to Autoimmune Diseases

V-ets erythroblastosis virus E26 oncogene homolog 1 (ETS1) is recognized as a gene of risk to autoimmune diseases (ADs). Two single nucleotide polymorphisms (SNPs) in ETS1 (rs1128334 G\u3eA and rs10893872 T\u3eC) were considered associated with ADs risk. However, the results remain conflicting. We performed a meta-analysis to evaluate more precise estimations of any relationship. We searched PubMed, OvidSP, and Chinese National Knowledge Infrastructure databases (papers published prior to September 12, 2014) and extracted data from eligible studies. Meta-analysis was performed using the STATA 12.0 software. Random effect model or fixed effect model were chosen according to the study heterogeneities. A total of 11 studies including 7359 cases (9660 controls) for rs1128334 and 8 studies including 5419 cases (7122 controls) for rs10893872 were involved in this meta-analysis. Overall, our results showed that there were significant associations for rs1128334 with AD risk in 5 genetic models, both in pooled analysis and in systemic lupus erythematous (SLE) subgroup, and in 3 genetic models of the uveitis subgroup. Although for rs10893872, the results showed that there were significant associations in allele model both in pooled analysis and in SLE subgroup. As a conclusion, this meta-analysis demonstrated that these 2 SNPs (rs1128334 and rs10893872) in ETS1were associated with ADs risk

The tumor suppressor folliculin inhibits lactate dehydrogenase A and regulates the Warburg effect

Aerobic glycolysis in cancer cells, also known as the 'Warburg effect', is driven by hyperactivity of lactate dehydrogenase A (LDHA). LDHA is thought to be a substrate-regulated enzyme, but it is unclear whether a dedicated intracellular protein also regulates its activity. Here, we identify the human tumor suppressor folliculin (FLCN) as a binding partner and uncompetitive inhibitor of LDHA. A flexible loop within the amino terminus of FLCN controls movement of the LDHA active-site loop, tightly regulating its enzyme activity and, consequently, metabolic homeostasis in normal cells. Cancer cells that experience the Warburg effect show FLCN dissociation from LDHA. Treatment of these cells with a decapeptide derived from the FLCN loop region causes cell death. Our data suggest that the glycolytic shift of cancer cells is the result of FLCN inactivation or dissociation from LDHA. Together, FLCN-mediated inhibition of LDHA provides a new paradigm for the regulation of glycolysis.Identification of the tumor suppressor FLCN as an intracellular inhibitor of LDHA and a regulator of the Warburg effect provides a new paradigm for the regulation of glycolysis