A5056732528- Cholesterol and Lipid Metabolism
- Estrogen and related hormone effects
- Adipose Tissue and Metabolism
- Drug Transport and Resistance Mechanisms
- Hormonal Regulation and Hypertension
- Genetics, Aging, and Longevity in Model Organisms
- Peroxisome Proliferator-Activated Receptors
- Circadian rhythm and melatonin
- Liver Disease Diagnosis and Treatment
- RNA Research and Splicing
- Nuclear Receptors and Signaling
- Neurotransmitter Receptor Influence on Behavior
- Birth, Development, and Health
- Fibroblast Growth Factor Research
- Psychedelics and Drug Studies
- Lipid Membrane Structure and Behavior
- Steroid Chemistry and Biochemistry
- Kruppel-like factors research
- Endoplasmic Reticulum Stress and Disease
- Stress Responses and Cortisol
- Neuroscience and Neuropharmacology Research
- interferon and immune responses
- Genetic Syndromes and Imprinting
- Axon Guidance and Neuronal Signaling
- NF-κB Signaling Pathways
University of Toronto
2013-2024
Although widely prescribed for their potent antiinflammatory actions, glucocorticoid drugs (e.g., dexamethasone) cause undesirable side effects that are features of the metabolic syndrome, including hyperglycemia, fatty liver, insulin resistance, and type II diabetes. Liver x receptors (LXRs) nuclear respond to cholesterol metabolites regulate expression a subset target genes. Here, we show LXRβ is required mediate many negative glucocorticoids. Mice lacking (but not LXRα) were resistant...
Hormones such as fibroblast growth factor 21 (FGF21) and glucocorticoids (GCs) play crucial roles in coordinating the adaptive starvation response. Here we examine interplay between these hormones. It was previously shown that FGF21 induces corticosterone levels mice by acting on brain. We now show this expression of genes required for GC synthesis adrenal gland. also increases secretion from response to ACTH. further relationship GCs is bidirectional. induce Fgf21 liver receptor (GR). The...
Long term benefits following short-term administration of high psychedelic doses serotonergic and dissociative hallucinogens, typified by psilocybin ketamine respectively, support their potential as treatments for psychiatric conditions such major depressive disorder. The induce perceptual experiences which are associated with therapeutic benefit. There have also been anecdotal reports these drugs being used at what colloquially referred to “micro” improve mood cognitive function, although...
The nuclear receptor peroxisome proliferator-activated alpha (PPARα) is emerging as an important target in the brain for treatment or prevention of cognitive disorders. identification high-affinity ligands PPARα may reveal mechanisms underlying synaptic effects this and facilitate drug development. Here, using affinity purification–untargeted mass spectrometry (AP-UMS) approach, we identified endogenous, selective ligand, 7( S )-hydroxy-docosahexaenoic acid [7( )-HDHA]. Results from...
Bile acids are cholesterol-derived signaling molecules that regulate mammalian metabolism through sterol-sensing nuclear receptor transcription factors. In C. elegans, bile acid-like steroids called dafachronic (DAs) control developmental timing and longevity by activating the DAF-12. However, little is known about biosynthesis of these molecules. Here, we show DAF-36/Rieske oxygenase works at first committed step, converting cholesterol to 7-dehydrocholesterol. Its elucidation as a...
Endogenous small molecule metabolites that regulate animal longevity are emerging as a novel means to influence health and life span. In C. elegans, bile acid-like steroids called the dafachronic acids (DAs) developmental timing through conserved nuclear hormone receptor DAF-12, homolog of mammalian sterol-regulated receptors LXR FXR. Using metabolic genetics, mass spectrometry, biochemical approaches, we identify new activities in DA biosynthesis characterize an evolutionarily short chain...
Endothelial progenitor cells (EPCs), critical for mediating vascular repair, are dysfunctional in a hyperglycemic and/or hypercholesterolemic environment. Their dysfunction contributes to the progression of diabetic macro- and microvascular complications. Activation "cholesterol-sensing" nuclear receptors, liver X receptors (LXRα/LXRβ), protects against atherosclerosis by transcriptional regulation genes important promoting cholesterol efflux inhibiting inflammation. We hypothesized that LXR...
The prevalence of metabolic diseases is increasing globally at an alarming rate; thus, it essential that effective, accessible, low-cost therapeutics are developed. Peroxisome proliferator-activated receptors (PPARs) transcription factors tightly regulate glucose homeostasis and lipid metabolism important drug targets for the treatment type 2 diabetes dyslipidemia. We previously identified LDT409, a fatty acid-like compound derived from cashew nut shell liquid, as novel pan-active PPARα/γ/δ...
Metabolic diseases are increasing at staggering rates globally. The peroxisome proliferator-activated receptors (PPARα/γ/δ) fatty acid sensors that help mitigate imbalances between energy uptake and utilization. Herein, we report compounds derived from phenolic lipids present in cashew nut shell liquid (CNSL), an abundant waste byproduct, effort to create effective, accessible, sustainable drugs. Derivatives of anacardic cardanol were tested for PPAR activity HEK293 cell co-transfection...
ABSTRACT Current peroxisome proliferator-activated receptor (PPAR)-targeted drugs, such as the PPARγ-directed diabetes drug rosiglitazone, are associated with undesirable side effects due to robust agonist activity in non-target tissues. To find new PPAR ligands fewer toxic effects, we generated transgenic zebrafish that can be screened high throughput for tissue-selective partial agonists. A structural analog of coenzyme Q10 (idebenone) elicits spatially restricted both PPARα and PPARγ was...
Stress hormones bind and activate the glucocorticoid receptor (GR) in many tissues including brain. We identified arginine glutamate rich 1 (ARGLU1) a screen for new modulators of signaling CNS. Biochemical studies show that C-terminus ARGLU1 coactivates multiple nuclear receptors N-terminus interacts with splicing factors binds to RNA. RNA-seq neural cells depleted revealed significant changes expression alternative distinct genes involved neurogenesis. Loss is embryonic lethal mice,...
Abstract Hepatic ABC efflux transporters control the cellular uptake (in basolateral membranes) and excretion apical of many substrates. Since type‐1 diabetes mellitus (T1DM) is associated with altered hepatobiliary endogenous exogenous substances, we examined key hepatic levels substrate glutathione in rats acute streptozotocin‐induced T1DM. Renal inflammatory markers were also examined. Abcb1, Abcc1–4 , Abcg2 measured using qRT‐PCR. Glutathione was liver tissue, plasma, urine. Inflammatory...
Synthetic glucocorticoids (GCs), including dexamethasone (DEX), are powerful anti-inflammatory drugs. Long-term use of GCs, however, can result in metabolic side effects such as hyperglycemia, hepatosteatosis, and insulin resistance. The GC receptor (GR) liver X receptors (LXRα LXRβ) regulate overlapping genes involved gluconeogenesis inflammation. We have previously shown that Lxrβ−/− mice resistant to the diabetogenic DEX but still sensitive its immunosuppressive actions. To determine...
Abstract The nematode Caenorhabditis elegans is a bacterivore filter feeder. Through the contraction of worm’s pharynx, bacterial suspension sucked into pharynx’s lumen. Excess liquid then shunted out buccal cavity through ancillary channels made by surrounding marginal cells. We find that many worm-bioactive small molecules ( a.k.a . wactives) accumulate inside cells as crystals or globular spheres. screens for mutants resist lethality associated with one crystallizing wactive we identify...
Aim Omega‐3 fatty acid ethyl ester supplements, available by prescription, are common in the treatment of dyslipidaemia humans. Recent studies show that 3‐carboxy‐4‐methyl‐5‐propyl‐2‐furanpropanoic (CMPF), a metabolite formed from fish oil supplementation, was able to prevent and reverse high fat diet (HFD)‐induced liver mice. In present study, we investigated underlying molecular mechanisms responsible for CMPF's hepatic lipid‐lowering effects. Materials Methods CD1 male mice were i.p....
Wistar-Kyoto (WKY) rats exhibit depression-like characteristics and decreased sensitivity to monoamine-based antidepressants, making them a suitable model of treatment-resistant depression (TRD). Ketamine has emerged recently as rapidly acting antidepressant with high efficacy in TRD. Our aim was determine whether subanaesthetic doses ketamine can correct sleep electroencephalogram (EEG) alterations WKY any ketamine-induced changes differentially affect compared Sprague-Dawley (SD) rats....