Search results for "mTOR pathway"
showing 6 items of 226 documents
Insulin resistance aggravates atherosclerosis by reducing vascular smooth muscle cell survival and increasing CX3CL1/CX3CR1 axis.
2014
Aims Insulin resistance (IR) is a major risk factor for cardiovascular disease and atherosclerosis. Life-threatening acute events are mainly due to rupture of unstable plaques, and the role of vascular smooth muscle cells (VSMCs) in this process in IR, Type 2 diabetes mellitus, and metabolic syndrome (T2DM/MetS) has not been fully addressed. Therefore, the role of VSMC survival in the generation of unstable plaques in T2DM/MetS and the involvement of inflammatory mediators was investigated. Methods and results Defective insulin receptor substrate 2 (IRS2)-mediated signalling produced insulin-resistant VSMCs with reduced survival, migration, and higher apoptosis than control cells. Silencing…
Lipid Activates mTORC1 and mTORC2 in the Absorption of Dietary Triglycerides
2018
Mechanistic target of rapamycin (mTOR) senses amino acids; however, its role in lipid metabolism is less established. Organismal lipid requirements are largely met through dietary intake. How nutrient sensing mechanisms in gut interface with dietary fat remains unclear. Here we reveal fundamental and cooperative roles for mTOR complexes 1 and 2 (mTORC1/2) in absorption of dietary triglycerides. Dietary lipid activates mTORC1/2 signaling in gut. Hyperactivating mTORC1 by deleting Tsc1 is sufficient to promote triglyceride absorption and metabolic disease in high fat-fed mice. Conversely, blocking mTORC1/2 by deleting Raptor or Rictor each decreases triglyceride absorption. Loss of Raptor seq…
FRI0150 Mtor blockade by rapamycin decreases arthritis and spondylitis development and severity in hla-b27 transgenic rats
2018
Career situation of first and presenting author Student for a master or a PhD. Introduction TNF and IL-17A have been demonstrated as key inflammatory cytokines in Spondyloarthritis (SpA), whereas targeting bone remodeling remains an unmet clinical need in SpA. The mammalian target of rapamycin (mTOR) regulates IL-17 expression and osteogenesis and could therefore be a promising therapeutic target in SpA. Objectives To investigate if blockade of mTOR with rapamycin inhibits the pathological processes in inflammation and bone in SpA. Methods Cytokines were measured by ELISA in the supernatant from SpA patient PBMCs stimulated with anti-CD3/CD28, with various concentrations of rapamycin. SpA F…
Targeting GSK3 and Associated Signaling Pathways Involved in Cancer
2020
Glycogen synthase kinase 3 (GSK-3) is a serine/threonine (S/T) protein kinase. Although GSK-3 originally was identified to have functions in regulation of glycogen synthase, it was subsequently determined to have roles in multiple normal biochemical processes as well as various disease conditions. GSK-3 is sometimes referred to as a moonlighting protein due to the multiple substrates and processes which it controls. Frequently, when GSK-3 phosphorylates proteins, they are targeted for degradation. GSK-3 is often considered a component of the PI3K/PTEN/AKT/GSK-3/mTORC1 pathway as GSK-3 is frequently phosphorylated by AKT which regulates its inactivation. AKT is often active in human cancer a…
A novel microtubule de-stabilizing complementarity-determining region C36L1 peptide displays antitumor activity against melanoma in vitro and in vivo
2015
AbstractShort peptide sequences from complementarity-determining regions (CDRs) of different immunoglobulins may exert anti-infective, immunomodulatory and antitumor activities regardless of the specificity of the original monoclonal antibody (mAb). In this sense, they resemble early molecules of innate immunity. C36L1 was identified as a bioactive light-chain CDR1 peptide by screening 19 conserved CDR sequences targeting murine B16F10-Nex2 melanoma. The 17-amino acid peptide is readily taken up by melanoma cells and acts on microtubules causing depolymerization, stress of the endoplasmic reticulum and intrinsic apoptosis. At low concentrations, C36L1 inhibited migration, invasion and proli…
MTOR inhibitor-based combination therapies for pancreatic cancer
2018
Background: Although the mechanistic target of rapamycin (MTOR) kinase, included in the mTORC1 and mTORC2 signalling hubs, has been demonstrated to be active in a significant fraction of patients with pancreatic ductal adenocarcinoma (PDAC), the value of the kinase as a therapeutic target needs further clarification. Methods: We used Mtor floxed mice to analyse the function of the kinase in context of the pancreas at the genetic level. Using a dual-recombinase system, which is based on the flippase-FRT (Flp-FRT) and Cre-loxP recombination technologies, we generated a novel cellular model, allowing the genetic analysis of MTOR functions in tumour maintenance. Cross-species validation and pha…