Identification of dual PPARα/γ agonists and their effects on lipid metabolism

Gao, Quanqing; Hanh, Jacky; Váradi, Linda; Cairns, Rose; Sjöström, Helena; Liao, Vivian W Y; Wood, Peta; Balaban, Seher; Ong, Jennifer; Lin, Hsuan-Yu; Lai, Felcia; Hoy, Andrew J.; Grewal, Thomas; Groundwater, Paul W.; Hibbs, David E.

doi:10.1016/j.bmc.2015.11.013

Cited by 14 publications

(6 citation statements)

References 52 publications

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“…In detail, endothelial lipase (EL; LIPG) plays a key role in atherosclerosis, and is actively investigated as a modulator in inflammatory processes and cancer [30,31], with examples of inhibitors of natural origin targeting closely related triacyglycerol lipases [32,33]. PPARα is a validated target for intervention in several therapeutic areas, including inflammation, diabetes, metabolic disorders and atherosclerosis [34,35], with specific agonists isolated from natural sources [36,37]. PTP1B acts as a negative regulator for the insulin signalling pathway and a drug target for the treatment of type II diabetes [38].…”

Section: Resultsmentioning

confidence: 99%

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Exploring the Chemical Space of Macro- and Micro-Algae Using Comparative Metabolomics

et al. 2021

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With more than 156,000 described species, eukaryotic algae (both macro- and micro-algae) are a rich source of biological diversity, however their chemical diversity remains largely unexplored. Specialised metabolites with promising biological activities have been widely reported for seaweeds, and more recently extracts from microalgae have exhibited activity in anticancer, antimicrobial, and antioxidant screens. However, we are still missing critical information on the distinction of chemical profiles between macro- and microalgae, as well as the chemical space these metabolites cover. This study has used an untargeted comparative metabolomics approach to explore the chemical diversity of seven seaweeds and 36 microalgal strains. A total of 1390 liquid chromatography-mass spectrometry (LC-MS) features were detected, representing small organic algal metabolites, with no overlap between the seaweeds and microalgae. An in-depth analysis of four Dunaliella tertiolecta strains shows that environmental factors may play a larger role than phylogeny when classifying their metabolomic profiles.

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Section: Resultsmentioning

confidence: 99%

“…nists isolated from natural sources [36,37]. PTP1B acts as a negative regulator for the insulin signalling pathway and a drug target for the treatment of type II diabetes [38].…”

Section: Resultsmentioning

confidence: 99%

Exploring the Chemical Space of Macro- and Micro-Algae Using Comparative Metabolomics

et al. 2021

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“…While less in known about the therapeutic uses of CBGA compared with the other minor cannabinoids, it may play a role in controlling diabetes mellitus and preventing the cardiovascular complications that can accompany Type 2 diabetes ( D'Aniello, et al, 2019 ). Through activation of PPARs, CBGA can improve lipid metabolism and reduce the accumulation of adipose tissue; thus reducing insulin resistance in the Type 2 patient ( Gao, et al, 2015 ). Type 2 diabetes is considered a “coronary artery disease equivalent” and mortality in Type 2 diabetes primarily results from cardiovascular events including acute coronary syndrome (ACS).…”

Section: Minor Cannabinoid Pharmacology and Therapeuticsmentioning

confidence: 99%

Minor Cannabinoids: Biosynthesis, Molecular Pharmacology and Potential Therapeutic Uses

2021

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The medicinal use of Cannabis sativa L. can be traced back thousands of years to ancient China and Egypt. While marijuana has recently shown promise in managing chronic pain and nausea, scientific investigation of cannabis has been restricted due its classification as a schedule 1 controlled substance. A major breakthrough in understanding the pharmacology of cannabis came with the isolation and characterization of the phytocannabinoids trans-Δ9-tetrahydrocannabinol (Δ9-THC) and cannabidiol (CBD). This was followed by the cloning of the cannabinoid CB1 and CB2 receptors in the 1990s and the subsequent discovery of the endocannabinoid system. In addition to the major phytocannabinoids, Δ9-THC and CBD, cannabis produces over 120 other cannabinoids that are referred to as minor and/or rare cannabinoids. These cannabinoids are produced in smaller amounts in the plant and are derived along with Δ9-THC and CBD from the parent cannabinoid cannabigerolic acid (CBGA). While our current knowledge of minor cannabinoid pharmacology is incomplete, studies demonstrate that they act as agonists and antagonists at multiple targets including CB1 and CB2 receptors, transient receptor potential (TRP) channels, peroxisome proliferator-activated receptors (PPARs), serotonin 5-HT1a receptors and others. The resulting activation of multiple cell signaling pathways, combined with their putative synergistic activity, provides a mechanistic basis for their therapeutic actions. Initial clinical reports suggest that these cannabinoids may have potential benefits in the treatment of neuropathic pain, neurodegenerative diseases, epilepsy, cancer and skin disorders. This review focuses on the molecular pharmacology of the minor cannabinoids and highlights some important therapeutic uses of the compounds.

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“…Side‐effects are mostly accompanied by single PPAR activation, so agonists of multitargeted PPARs for the development of metabolic disorders were in hot research. Agents activating PPARα displayed decreased effects on lipid while activation of PPARγ would regulate the adipocyte differentiation and enhance insulin sensitivity . Therefore, the adverse effects such as obesity could be reduced by the corporation of PPARα and PPARγ activation, namely PPARα/γ dual activation.…”

Section: Dual Pparα/γ Agonistsmentioning

confidence: 99%

Multitargeted bioactive ligands for PPARs discovered in the last decade

et al. 2016

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Type 2 diabetes took insulin resistance as the main clinical manifestation. PPARs have been reported to be the therapeutic targets of metabolic disorders, such as obesity, hypertension, diabetes, and cardiovascular disease. Previously, PPARγ agonist rosiglitazone was restricted in clinic due to cardiomyocytes infarction, weight gain, and other serious side-effects, which were mainly due to the single and selective PPARγ agonism. In recent years, multitarget-directed PPAR agonists with synergistic reaction as well as fewer side-effect have been the hot topic in designing promising agents. In this review, we updated and generalized the development of PPARγ partial agonists, PPARγ antagonists, PPARα/γ dual agonists, PPARδ partial agonists, PPARδ antagonists, PPARα/δ dual agonists, PPARγ/δ dual agonists, and PPARα/γ/δ pan-agonists published in recent decade. Most of these molecules were modified from known structures or came from high-throughput screening. Among these molecules, some were expected to be promising drugs against metabolic disorders, while others seemed to provide new insight for designing novel PPAR agents.

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Identification of dual PPARα/γ agonists and their effects on lipid metabolism

Cited by 14 publications

References 52 publications

Exploring the Chemical Space of Macro- and Micro-Algae Using Comparative Metabolomics

Exploring the Chemical Space of Macro- and Micro-Algae Using Comparative Metabolomics

Minor Cannabinoids: Biosynthesis, Molecular Pharmacology and Potential Therapeutic Uses

Multitargeted bioactive ligands for PPARs discovered in the last decade

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