ABSTRACT
BACKGROUND: Activation of brown adipose tissue (BAT) has gained attention due to its ability to dissipate energy and counteract cardiometabolic diseases (CMDs). METHODS: This study investigated the consequences of cold exposure on the BAT and liver proteomes of an established CMD mouse model based on LDL receptor-deficient (LdlrKO) mice fed a high-fat, high-sucrose, high-cholesterol diet for 16 weeks. We analyzed energy metabolism in vivo and performed untargeted proteomics on BAT and liver of LdlrKO mice maintained at 22 °C or 5 °C for 7 days. RESULTS: We identified several dysregulated pathways, miRNAs, and transcription factors in BAT and liver of cold-exposed Ldlrko mice that have not been previously described in this context. Networks of regulatory interactions based on shared downstream targets and analysis of ligand-receptor pairs identified fibrinogen alpha chain (FGA) and fibronectin 1 (FN1) as potential crosstalk factors between BAT and liver in response to cold exposure. Importantly, genetic variations in the genes encoding FGA and FN1 have been associated with cardiometabolic-related phenotypes and traits in humans. DISCUSSION: This study describes the key factors, pathways, and regulatory networks involved in the crosstalk between BAT and the liver in a cold-exposed CMD mouse model. These findings may provide a basis for future studies aimed at testing whether molecular mediators, as well as regulatory and signaling mechanisms involved in tissue adaption upon cold exposure, could represent a target in cardiometabolic disorders.
Subject(s)
Adipose Tissue, Brown , Cold Temperature , Disease Models, Animal , Energy Metabolism , Gene Regulatory Networks , Liver , Mice, Knockout , Proteomics , Receptors, LDL , Signal Transduction , Animals , Adipose Tissue, Brown/metabolism , Liver/metabolism , Energy Metabolism/genetics , Receptors, LDL/genetics , Receptors, LDL/metabolism , Receptors, LDL/deficiency , Male , Fibrinogen/metabolism , Fibrinogen/genetics , Mice, Inbred C57BL , MicroRNAs/metabolism , MicroRNAs/genetics , Fibronectins/metabolism , Fibronectins/genetics , Transcription Factors/genetics , Transcription Factors/metabolism , Mice , Gene Expression Regulation , Protein Interaction MapsABSTRACT
Piezo1, a mechano-activated ion channel, has wide-ranging physiological and therapeutic implications, with the ongoing development of specific agonists unveiling cellular responses to mechanical stimuli. In our study, we systematically analyzed the chemical subunits in Piezo1 protein agonist Yoda1 to comprehend the structure-activity relationship and push forward next-generation agonist development. Preliminary screening assays for Piezo1 agonism were performed using the Piezo1-mCherry-transfected HEK293A cell line, keeping Yoda1 as a positive control. We introduce a novel Piezo1 agonist Yaddle1 (34, 0.40 µM), featuring a trifluoromethyl group, with further exploration through in vitro studies and density functional theory calculations, emphasizing its tetrel interactions, to act as an ambidextrous wedge between the domains of Piezo1. In contrast to the poor solubility of the established agonist Yoda1, our results showed that the kinetic solubility of Yaddle1 (26.72 ± 1.8 µM at pH 7.4) is 10-fold better than that of Yoda1 (1.22 ± 0.11 µM at pH 7.4). Yaddle1 (34) induces Ca2+ influx in human CD4+ T cell, suggesting its potential as a vaccine adjuvant for enhanced T cell activation.
Subject(s)
Ion Channels , T-Lymphocytes , Humans , Ion Channels/metabolism , HEK293 Cells , Structure-Activity Relationship , T-Lymphocytes/drug effects , T-Lymphocytes/immunology , T-Lymphocytes/metabolism , Adjuvants, Immunologic/pharmacology , Adjuvants, Immunologic/chemistry , Lymphocyte Activation/drug effects , Pyrazines , ThiadiazolesABSTRACT
Visceral leishmaniasis is a potentially fatal disease caused by infection by the intracellular protist pathogens Leishmania donovani or Leishmania infantum. Present therapies are ineffective because of high costs, variable efficacy against different species, the requirement for hospitalization, toxicity and drug resistance. Detailed analysis of previously published hit molecules suggested a crucial role of 'guanidine' linkage for their efficacy against L. donovani. Here we report the design of 2-aminoquinazoline heterocycle as a basic pharmacophore-bearing guanidine linkage. The introduction of various groups and functionality at different positions of the quinazoline scaffold results in enhanced antiparasitic potency with modest host cell cytotoxicity using a physiologically relevant THP-1 transformed macrophage infection model. In terms of the ADME profile, the C7 position of quinazoline was identified as a guiding tool for designing better molecules. The good ADME profile of the compounds suggests that they merit further consideration as lead compounds for treating visceral leishmaniasis.