Whole-blood transcriptome profiling reveals signatures of metformin and its therapeutic response
PLOS ONE
Authors: Ustinova, Monta; Ansone, Laura; Silamikelis, Ivars; Rovite, Vita; Elbere, Ilze; Silamikele, Laila; Kalnina, Ineta; Fridmanis, Davids; Sokolovska, Jelizaveta; Konrade, Ilze; Pirags, Valdis; Klovins, Janis
Abstract
Metformin, a biguanide agent, is the first-line treatment for type 2 diabetes mellitus due to its glucose-lowering effect. Despite its wide application in the treatment of multiple health conditions, the glycemic response to metformin is highly variable, emphasizing the need for reliable biomarkers. We chose the RNA-Seq-based comparative transcriptomics approach to evaluate the systemic effect of metformin and highlight potential predictive biomarkers of metformin response in drug-naive volunteers with type 2 diabetesin vivo. The longitudinal blood-derived transcriptome analysis revealed metformin-induced differential expression of novel and previously described genes involved in cholesterol homeostasis (SLC46A1andLRP1), cancer development(CYP1B1,STAB1,CCR2,TMEM176B), and immune responses (CD14,CD163) after administration of metformin for three months. We demonstrate for the first time a transcriptome-based molecular discrimination between metformin responders (delta HbA1c >= 1% or 12.6 mmol/mol) and non-responders (delta HbA1c < 1% or 12.6 mmol/mol), that is determined by expression levels of 56 genes, explaining 13.9% of the variance in the therapeutic efficacy of the drug. Moreover, we found a significant upregulation ofIRS2gene (log(2)FC 0.89) in responders compared to non-responders before the use of metformin. Finally, we provide evidence for the mitochondrial respiratory complex I as one of the factors related to the high variability of the therapeutic response to metformin in patients with type 2 diabetes mellitus.
Expression of Enamel Proteins in Human Dental Pulp Stem Cells by the Effect of extracellular Matrix
INTERNATIONAL JOURNAL OF MORPHOLOGY
Authors: Salazar-de Santiago, Alfredo; Avelar-Gonzalez, Francisco J.; Manuel Diaz, Juan; Campos-Navarro, Paloma M.; Flores-Villalpado, Elizz M.; Hernandez-Cuellar, Edgar E.; Guerrero-Barrera, Alma L.
Abstract
Mesenchymal stem cells are present in adult tissues such as the human dental pulp. They are pluripotent and can differentiate into various specialized cell types in vitro through appropriate stimuli. Ameloblasts produce human tooth enamel only during embryonic development before tooth eruption, so endogenous regeneration is not possible. Various efforts have been aimed at generating natural or artificial substitutes for dental enamel with properties similar to the specific components of said tissue. The purpose of this study was to induce human dental pulp stem cells to produce enamel proteins using extracellular matrix derived from the rat tail tendon and pigskin. Primary cultures of human dental pulp stem cells were established and characterized by RT-PCR and immunofluorescence, using mesenchymal cell markers such as CD14, CD40, CD44, CD105, and STRO-1. The cells were then incubated with the extracellular matrix for fourteen days and labeled with specific antibodies to detect the expression of dental enamel proteins such as amelogenin, ameloblastin, enamelisin, tuftelin, and parvalbumin, characteristics of the phenotype of ameloblasts. This work demonstrated a positive effect of the extracellular matrix to induce the expression of enamel proteins in the stem cells of the human dental pulp.