Search results for "RAPAMYCIN"
showing 10 items of 44 documents
Metformin influences drug sensitivity in pancreatic cancer cells
2018
Abstract Pancreatic ductal adenocarcinoma (PDAC) is an aggressive, highly metastatic malignancy and accounts for 85% of pancreatic cancers. PDAC patients have poor prognosis with a five-year survival of only 5–10% after diagnosis and treatment. Pancreatic cancer has been associated with type II diabetes as the frequency of recently diagnosed diabetics that develop pancreatic cancer within a 10-year period of initial diagnosis of diabetes in increased in comparison to non-diabetic patients. Metformin is a very frequently prescribed drug used to treat type II diabetes. Metformin acts in part by stimulating AMP-kinase (AMPK) and results in the suppression of mTORC1 activity and the induction o…
Effect of Sirolimus Exposure on the Need for Preemptive Antiviral Therapy for Cytomeglovirus Infection after Allogeneic Hematopoietic Stem Cell Trans…
2019
The current study evaluates the clinical effect of sirolimus exposure on the occurrence of cytomegalovirus (CMV) DNAemia necessitating preemptive antiviral therapy. A total of 167 consecutive recipients of reduced-intensity conditioning (RIC) allogeneic hematopoietic stem cell transplantation (allo-HSCT) who received sirolimus- and tacrolimus-based graft-versus-host disease (GVHD) prophylaxis and whose CMV serostatus was positive for donors and/or recipients were included in this multicenter retrospective study. A parametric model with consecutive sirolimus blood levels describing the time to CMV DNAemia-RAT was developed using NONMEM version 7.4. Overall, 122 of 167 patients (73%) were all…
Ectopic NGAL expression can alter sensitivity of breast cancer cells to EGFR, Bcl-2, CaM-K inhibitors and the plant natural product berberine
2012
Neutrophil gelatinase-associated lipocalin (NGAL, a.k.a Lnc2) is a member of the lipocalin family and has diverse roles. NGAL can stabilize matrix metalloproteinase-9 from autodegradation. NGAL is considered as a siderocalin that is important in the transport of iron. NGAL expression has also been associated with certain neoplasias and is implicated in the metastasis of breast cancer. In a previous study, we examined whether ectopic NGAL expression would alter the sensitivity of breast epithelial, breast and colorectal cancer cells to the effects of the chemotherapeutic drug doxorubicin. While abundant NGAL expression was detected in all the cells infected with a retrovirus encoding NGAL, t…
TORC1 coordinates the conversion of Sic1 from a target to an inhibitor of cyclin-CDK-Cks1
2017
Eukaryotic cell cycle progression through G(1)-S is driven by hormonal and growth-related signals that are transmitted by the target of rapamycin complex 1 (TORC1) pathway. In yeast, inactivation of TORC1 restricts G(1)-S transition due to the rapid clearance of G(1) cyclins (Cln) and the stabilization of the B-type cyclin (Clb) cyclin-dependent kinase (CDK) inhibitor Sic1. The latter mechanism remains mysterious but requires the phosphorylation of Sic1-Thr(173) by Mpk1 and inactivation of the Sic1-pThr(173)-targeting phosphatase (PP2A(Cdc55)) through greatwall kinase-activated endosulfines. Here we show that the Sic1-pThr(173) residue serves as a specific docking site for the CDK phospho-a…
TORC1 controls G1–S cell cycle transition in yeast via Mpk1 and the greatwall kinase pathway
2015
The target of rapamycin complex 1 (TORC1) pathway couples nutrient, energy and hormonal signals with eukaryotic cell growth and division. In yeast, TORC1 coordinates growth with G1–S cell cycle progression, also coined as START, by favouring the expression of G1 cyclins that activate cyclin-dependent protein kinases (CDKs) and by destabilizing the CDK inhibitor Sic1. Following TORC1 downregulation by rapamycin treatment or nutrient limitation, clearance of G1 cyclins and C-terminal phosphorylation of Sic1 by unknown protein kinases are both required for Sic1 to escape ubiquitin-dependent proteolysis prompted by its flagging via the SCFCdc4 (Skp1/Cul1/F-box protein) ubiquitin ligase complex.…
Rapamycin-Loaded Polymeric Nanoparticles as an Advanced Formulation for Macrophage Targeting in Atherosclerosis
2021
Recently, rapamycin (Rapa) represents a potential drug treatment to induce regression of atherosclerotic plaques
A genome-wide transcriptional study reveals that iron deficiency inhibits the yeast TORC1 pathway
2019
Iron is an essential micronutrient that participates as a cofactor in a broad range of metabolic processes including mitochondrial respiration, DNA replication, protein translation and lipid biosynthesis. Adaptation to iron deficiency requires the global reorganization of cellular metabolism directed to optimize iron utilization. The budding yeast Saccharomyces cerevisiae has been widely used to characterize the responses of eukaryotic microorganisms to iron depletion. In this report, we used a genomic approach to investigate the contribution of transcription rates to the modulation of mRNA levels during adaptation of yeast cells to iron starvation. We reveal that a decrease in the activity…
mTORC1 activation in B cells confers impairment of marginal zone microarchitecture by exaggerating cathepsin activity
2018
Mammalian target of rapamycin complex 1 (mTORC1) is a key regulator of cell metabolism and lymphocyte proliferation. It is inhibited by the tuberous sclerosis complex (TSC), a heterodimer of TSC1 and TSC2. Deletion of either gene results in robust activation of mTORC1. Mature B cells reside in the spleen at two major anatomical locations, the marginal zone (MZ) and follicles. The MZ constitutes the first line of humoral response against blood‐borne pathogens and undergoes atrophy in chronic inflammation. In previous work, we showed that mice deleted for TSC1 in their B cells (TSC1(BKO)) have almost no MZ B cells, whereas follicular B cells are minimally affected. To explore potential underl…
Influences of TP53 and the anti-aging DDR1 receptor in controlling Raf/MEK/ERK and PI3K/Akt expression and chemotherapeutic drug sensitivity in prost…
2020
Background TP53 plays critical roles in sensitivity to chemotherapy, and aging. Collagen is very important in aging. The molecular structure and biochemical properties of collagen changes during aging. The discoidin domain receptor (DDR1) is regulated in part by collagen. Elucidating the links between TP53 and DDR1 in chemosensitivity and aging could improve therapies against cancer and aging. Results Restoration of WT-TP53 activity resulted in increased sensitivity to chemotherapeutic drugs and elevated expression of key components of the Raf/MEK/ERK, PI3K/Akt and DDR1 pathways. DDR1 could modulate the levels of Raf/MEK/ERK and PI3K/Akt pathways as well as sensitize the cells to chemothera…
Muscle follistatin gene delivery increases muscle protein synthesis independent of periodical physical inactivity and fasting
2020
Blocking of myostatin and activins effectively counteracts muscle atrophy. However, the potential interaction with physical inactivity and fasting in the regulation of muscle protein synthesis is poorly understood. We used blockade of myostatin and activins by recombinant adeno-associated virus (rAAV)-mediated follistatin (FS288) overexpression in mouse tibialis anterior muscle. To investigate the effects on muscle protein synthesis, muscles were collected 7 days after rAAV-injection in the nighttime or in the daytime representing high and low levels of activity and feeding, respectively, or after overnight fasting, refeeding, or ad libitum feeding. Muscle protein synthesis was increased by…