A5040872071- Metabolism, Diabetes, and Cancer
- Pancreatic function and diabetes
- Immune cells in cancer
- Adipose Tissue and Metabolism
- Neutrophil, Myeloperoxidase and Oxidative Mechanisms
- Diet and metabolism studies
- Liver Disease Diagnosis and Treatment
- GDF15 and Related Biomarkers
- Nutrition and Health in Aging
- Adipokines, Inflammation, and Metabolic Diseases
- Diabetes Treatment and Management
- interferon and immune responses
- Diet, Metabolism, and Disease
- Atherosclerosis and Cardiovascular Diseases
- Immune Cell Function and Interaction
- Mast cells and histamine
- Immune responses and vaccinations
- Diabetes and associated disorders
- Natural Antidiabetic Agents Studies
- COVID-19 Clinical Research Studies
- Diabetes Management and Research
- Nuclear Receptors and Signaling
- Macrophage Migration Inhibitory Factor
- Autophagy in Disease and Therapy
- Cancer, Lipids, and Metabolism
Trinity College Dublin
2021-2025
McMaster University
2015-2025
Western University
2025
Toronto Public Health
2023
Abstract Despite widespread use of statins to reduce low-density lipoprotein cholesterol (LDL-C) and associated atherosclerotic cardiovascular risk, many patients do not achieve sufficient LDL-C lowering due muscle-related side effects, indicating novel treatment strategies are required. Bempedoic acid (ETC-1002) is a small molecule intended lower in hypercholesterolemic patients, has been previously shown modulate both ATP-citrate lyase (ACL) AMP-activated protein kinase (AMPK) activity...
Canagliflozin, dapagliflozin, and empagliflozin, all recently approved for treatment of type 2 diabetes, were derived from the natural product phlorizin. They reduce hyperglycemia by inhibiting glucose reuptake sodium/glucose cotransporter (SGLT) in kidney, without affecting intestinal uptake SGLT1. We now report that canagliflozin also activates AMPK, an effect seen with phloretin (the aglycone breakdown phlorizin), but not to any significant extent or AMPK activation occurred at...
Abstract Metformin, a widely used first-line treatment for type 2 diabetes (T2D), is known to reduce blood glucose levels and suppress appetite. Here we report significant elevation of the appetite-suppressing metabolite N -lactoyl phenylalanine (Lac-Phe) in individuals treated with metformin across seven observational interventional studies. Furthermore, Lac-Phe were found rise response acute administration post-prandially patients T2D or metabolically healthy volunteers.
Metformin is the mainstay therapy for type 2 diabetes (T2D) and many patients also take salicylate-based drugs [i.e., aspirin (ASA)] cardioprotection. salicylate both increase AMP-activated protein kinase (AMPK) activity but by distinct mechanisms, with metformin altering cellular adenylate charge (increasing AMP) interacting directly at AMPK β1 drug-binding site. activation results in phosphorylation of ACC (acetyl-CoA carboxylase; P-ACC) inhibition acetyl-CoA carboxylase (ACC), rate...
Dysregulation of hepatic lipid and cholesterol metabolism is a significant contributor to cardiometabolic health, resulting in excessive liver accumulation ultimately non-alcoholic steatohepatitis (NASH). Therapeutic activators the AMP-Activated Protein Kinase (AMPK) have been proposed as treatment for metabolic diseases; we show that AMPK β1-biased activator PF-06409577 capable lowering systemic levels both rodent monkey preclinical models. able inhibit de novo synthesis pathways, causes...
Abstract Obesity results from a caloric imbalance between energy intake, absorption and expenditure. In both rodents humans, diet-induced thermogenesis contributes to expenditure involves the activation of brown adipose tissue (BAT). We hypothesize that environmental toxicants commonly used as food additives or pesticides might reduce BAT through suppression uncoupling protein 1 (UCP1) this may contribute development obesity. Using step-wise screening approach, we discover organophosphate...
Excessive inflammation-associated coagulation is a feature of infectious diseases, occurring in such conditions as bacterial sepsis and COVID-19. It can lead to disseminated intravascular coagulation, one the leading causes mortality worldwide. Recently, type I interferon (IFN) signaling has been shown be required for tissue factor (TF; gene name F3) release from macrophages, critical initiator providing an important mechanistic link between innate immunity coagulation. The mechanism...
The cytokine interleukin-10 (IL-10) limits the immune response and promotes resolution of acute inflammation. Because its immunosuppressive effects, IL-10 up-regulation is a common feature tumor progression metastasis. Recently, regulation has been shown to depend on mitochondria redox-sensitive signals. We have found that Suppressor site III Qo Electron Leak 1.2 (S3QEL 1.2), specific inhibitor reactive oxygen species (ROS) production from mitochondrial complex III, myxothiazol, inhibitor,...
Salsalate is a prodrug of salicylate that lowers blood glucose in patients with type 2 diabetes (T2D) and reduces nonalcoholic fatty liver disease (NAFLD) animal models; however, the mechanism mediating these effects unclear. Salicylate directly activates AMPK via β1 subunit, but whether salsalate requires AMPK-β1 to improve T2D NAFLD has not been examined. Therefore, wild-type (WT) AMPK-β1-knockout (AMPK-β1KO) mice were treated dose resulting clinically relevant serum concentrations (∼1...
Atherosclerosis stems from imbalances in lipid metabolism and leads to maladaptive inflammatory responses. The AMP-activated protein kinase (Ampk) is a highly conserved serine/threonine that regulates many aspects of energy metabolism, although its specific role controlling macrophage cholesterol homeostasis remains unclear. We sought address this question by testing the effects direct Ampk activators primary bone marrow-derived macrophages β1-deficient (β1(-/-)) mice. Macrophages β1(-/-)...
Abstract Neutrophils rely predominantly on glycolytic metabolism for their biological functions, including reactive oxygen species (ROS) production. Although pyruvate kinase M2 (PKM2) is a enzyme known to be involved in metabolic reprogramming and gene transcription many immune cell types, its role neutrophils remains poorly understood. Here, we report that PKM2 regulates ROS production microbial killing by neutrophils. Zymosan-activated showed increased cytoplasmic expression of PKM2....
Abstract Obesity is linked with insulin resistance and characterized by excessive accumulation of adipose tissue due to chronic energy imbalance. Increasing thermogenic brown beige futile cycling may be an important strategy increase expenditure in obesity, however, metabolic activity lower obesity. Herein, we report that the exposure mice thermoneutrality promotes infiltration white mast cells are highly enriched tryptophan hydroxylase 1 (Tph1), rate limiting enzyme regulating peripheral...
Fatty acids are vital for the survival of eukaryotes, but when present in excess can have deleterious consequences. The AMP-activated protein kinase (AMPK) is an important regulator multiple branches metabolism. Studies purified enzyme preparations and cultured cells shown that AMPK allosterically activated by small molecules as well fatty acyl-CoAs through a mechanism involving Ser108 within regulatory β1 isoform. However, vivo physiological significance this residue has not been evaluated....
The circadian rhythm of the immune system helps to protect against pathogens1–3; however, role rhythms in homeostasis is less well understood. Innate T cells are tissue-resident lymphocytes with key roles tissue homeostasis4–7. Here we use single-cell RNA sequencing, a molecular-clock reporter and genetic manipulations show that innate IL-17-producing cells—including γδ cells, invariant natural killer mucosal-associated cells—are enriched for genes compared their IFNγ-producing counterparts....
Sodium-glucose cotransporter 2 inhibitors such as canagliflozin lower blood glucose and reduce cardiovascular events in people with type diabetes through mechanisms that are not fully understood. Canagliflozin has been shown to increase the activity of AMP-activated protein kinase (AMPK), a metabolic energy sensor important for increasing fatty acid oxidation expenditure suppressing lipogenesis inflammation, but whether AMPK activation is mediating some beneficial effects determined. We,...
Growth differentiating factor-15 (GDF15) is an emerging target for the treatment of obesity and metabolic disease partly due to its ability suppress food intake. GDF15 expression secretion are thought be regulated by a cellular integrated stress response, which involves endoplasmic reticulum (ER) stress. AMPK another sensor, but relationship between AMPK, ER stress, has not been assessed in vivo. Wildtype (WT), β1 deficient (AMPKβ1-/- ), CHOP-/- mice were treated with three distinct...
Immune cells are metabolically plastic and respond to inflammatory stimuli with large shifts in metabolism. Itaconate is one of the most up-regulated metabolites macrophages response gram negative bacterial product LPS. As such, itaconate has recently been subject intense research interest. The artificial derivatives, including 4-Octyl (4-OI) Dimethyl (DI) naturally produced isomers, mesaconate citraconate, have tested relation biology similarities differences biochemistry immunomodulatory...
The pathogenic basis for increased thrombotic risk in individuals with inflammatory diseases is poorly understood. Myeloid cell “trained immunity” describes persistent innate immune memory arising from prior exposure to an stimulus, leading enhanced response subsequent unrelated stimuli. We identify myeloid prothrombotic activity as a maladaptive consequence of trained immunity. Lipopolysaccharide (LPS) stimulation macrophages previously β-glucan or heme exhibited significantly procoagulant...