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Molecular adaptations to endurance exercise and skeletal muscle fibre plasticity
Published in Adam P. Sharples, James P. Morton, Henning Wackerhage, Molecular Exercise Physiology, 2022
As with mitochondrial regulation by PGC-1α co-activating NRF1, fatty acid oxidation enzymes are regulated by PGC-1α co-activating the PPAR transcription factors. The primary PPAR in muscle is PPARβ/δ. In situations where there is low muscle glycogen, PPARδ activity is increased (85) and over time this can lead to an increase in the capacity to use fat as a fuel (86). As the name (PPARɣ co-activator) suggests, PGC-1α was discovered as a co-activator of the PPARs. Therefore, the increase in PGC-1α activity after exercise, through its co-activation of PPARδ, likely underlies the increase in fat oxidation that occurs with endurance training (87).
Mitochondrial Dysfunction and Oxidative Stress in the Pathogenesis of Metabolic Syndrome
Published in Shamim I. Ahmad, Handbook of Mitochondrial Dysfunction, 2019
Peroxisome proliferator-activated receptors (PPARs) are a family of nuclear receptors, which consists of three members, PPARα, PPARγ and PPARβ/δ. Among them, PPARα is expressed highly in tissues with high fatty acid oxidation (FAO) rates, such as liver, heart, skeletal muscle, brown adipose tissue, and kidney, although it is also universally expressed in other tissues, including the intestine, vascular endothelium, smooth muscle and immune cells78. PPARα is an essential nutritional sensor, which regulates transcription of genes involved in fatty acid (FA) catabolism, lipogenesis and ketone body synthesis, in response to feeding and starvation79. These include genes regulating mitochondrial β-oxidation, FA transport and hepatic glucose production80. Moreover, PPARα also displays anti-inflammatory properties by inhibiting pro-inflammatory and acute phase response (APR) signalling pathways, as evidenced by rodent models of systemic inflammation, atherosclerosis and non-alcoholic steatohepatitis (NASH)81,82.
The Cardiovascular System
Published in Pritam S. Sahota, James A. Popp, Jerry F. Hardisty, Chirukandath Gopinath, Page R. Bouchard, Toxicologic Pathology, 2018
Calvert Louden, David Brott, Chidozie J. Amuzie, Bindu Bennet, Ronnie Chamanza
The mechanistic basis for cardiotoxicity associated with some traditional NSAIDs, and the COX1-sparing but COX2-selective inhibitors, in high-risk patients, are not well understood (Cairns 2007; Vane and Warner 2000). In small vessel endothelium, during inflammation and angiogenesis, COX2 expression is stimulated by growth factors and cytokines (Crofford et al. 1994) in contrast to large vessels where laminar-shear causes COX2 to be expressed constitutively, presumably to maintain homeostasis. The emerging scientific data suggests that metabolism of endocannabinoids by endothelial COX2, coupled to prostacyclin synthase, activates the nuclear hormone receptor, peroxisomal proliferator-activated receptor delta (PPARδ). This activation in EC downregulates expression of tissue factor, the primary initiator of the coagulation cascade. The selective COX2 inhibitors suppress PPARδ activity and this suppression causes a loss of regulatory control of tissue factor expression in EC, causing marked elevation of circulating levels of tissue factor (Ghosh et al. 2007). The net effect is that in vivo, selective COX2 inhibitors increase endothelial as well as circulating levels of tissue factor through suppression of PPARδ, thus promoting thrombosis (Ghosh et al. 2007). Furthermore, PPARδ agonists are very effective in reversing this effect and returning tissue factor levels to within normal limits (Ghosh et al. 2007). Additionally, with the reduction in prostacyclin locally and systemically, there is an imbalance of thromboxane, leading to platelet aggregation and thrombosis.
Investigational drugs in early phase development for primary biliary cholangitis
Published in Expert Opinion on Investigational Drugs, 2021
Eric M. Gochanour, Kris V. Kowdley
PPAR has three unique isoforms – α, δ, and γ. PPARα, found in high concentration in the liver, induces expression of numerous genes involved in lipid and bile-acid metabolism as well as down-regulation of genes involved in immune-related pathways [42]. In cholangiocytes, PPARδ agonism has been shown to coordinate cholesterol flux and bile-acid metabolism via induction of ATP-binding cassette cholesterol transporter A1 (ABCA1) and Niemann-Pick C1-like L1 (NPC1L1) [43]. PPARδ also have a role in apoptotic cell elimination via macrophages, thus limiting the autoimmune response against self-antigens released by dying cells [44]. PPARγ, expressed in the intrahepatic biliary epithelium, inhibit pro-inflammatory cytokine production, and helps maintain bile-acid homeostasis [45]. PPARγ levels are decreased with bile duct damage [45]. It is hypothesized that replacement of PPARγ may diminish biliary inflammation in PBC and administration of PPARγ ligands has shown to significantly reduce portal inflammation and the number of T-cells in a mouse model of PBC [45,46].
Activation of epigenetic regulator KDM6B by Salmonella Typhimurium enables chronic infections
Published in Gut Microbes, 2021
Sarika Rana, Sonalika Maurya, Gayatree Mohapatra, Savita Singh, Rohan Babar, Hridya Chandrasekhar, Garima Chamoli, Deepak Rathore, Pallavi Kshetrapal, C. V. Srikanth
Chronic Salmonella infection has also been implicated in cancer cell transformation in genetically predisposed conditions. Thus, associating chronic Salmonella infection with colorectal and gallbladder cancer.4 The exact mechanism and pathophysiology of these diseases is still largely underexplored. Whether Salmonella infections, particularly chronic infections, also drive cancerous transformations of host as a result of epigenetic modifications remains an unanswered question. A recent study, wherein PPARδ was expressed under the control of villin-gene promoter in mice, has shown spontaneous development of invasive gastric adenocarcinomas highlighting the propensity of PPARδ to be carcinogenic.59 However, the role of PPARδ in APC heterozygous mice for development of colorectal cancer is quite controversial.60 KDM6B upregulation in intestinal crypts and PPARδ being its target and other identified WNT pathway genes, as shown in the above work, makes an interesting area of study in understanding long-term consequences of chronic Salmonella infection. Overall, the current study connects histone modifications and chromatin remodeling in Salmonella-host crosstalk, which may be critical for addressing some of the underexplored aspects of Salmonella pathogenicity such as chronic infections and long-term consequences of Salmonella infections including GBC.
Current status of GPR40/FFAR1 modulators in medicinal chemistry (2016–2019): a patent review
Published in Expert Opinion on Therapeutic Patents, 2020
Zheng Li, Zongtao Zhou, Luyong Zhang
The peroxisome proliferator-activated receptors (PPARs) have three subtypes: PPARα, PPARγ, and PPARδ. The PPARα or PPARγ agonist exhibited therapeutic benefits for glucose and lipid metabolism [77,78]. PPARδ is involved in lipid metabolism and inflammation, and considered as potent target of obesity and atherosclerosis [79]. It is worth mentioning that the endogenous ligands of FFAR1 and PPARs are free fatty acids, which provided the possibility to obtain multiple target agonists [80]. Indeed, several groups have reported some lead compounds (such as 53–56) with multiple potencies for FFAR1 and PPARs, though the activities are limited to micromolar levels [81–84]. CN102040517 has filed a series of resveratrol derivatives as quadruple PPARα/γ/δ and FFAR1 agonists, including compounds 53 and 54 [85]. Compound 53 could reduce oxidative stress, inflammation, lipid levels, and alleviate insulin resistance. In nonalcoholic steatohepatitis model, compound 53 significantly improved steatosis, inflammation and fibrosis of liver [86]. Based on hybrid strategy, the highly potent FFAR1/PPARδ agonists (such as 57 and 58) have been identified [87,88]. The dual agonist 57 significantly improved the glucose tolerance of ob/ob mice in a dose-dependent manner [87].