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Biocatalyzed Synthesis of Antidiabetic Drugs
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
PPAR-α agonists serves as cellular receptor for fibrates, a class of drugs used in the treatment of dyslipidemia, and also used for the treatment of vascular complications associated with Type 2 DM (Verges, 2004; Steiner, 2007). These fibrates possess a common chemical structure (2-methyl-2-aryloxypropionic acids or esters), not displaying any chiral center. In an attempt to obtain an enantiopure PPAR-α agonist, Astra Zeneca synthesized AZD 4619 ((S)-5, Fig. 11.9), an α agonist, by means of an enzymatic dynamic kinetic resolution (DKR) of the corresponding racemic thioester 4, using an organic base to promote the racemization (Brown et al., 2006), as shown in Fig. 11.9. DKR process to synthesize AZD 46919.
Diabetes and Antidiabetic Therapy: Control of Glucose
Published in Richard J. Sundberg, The Chemical Century, 2017
Two types of cells, the adipocytes and endothelium, are particularly important in insulin control of carbohydrate metabolism. Adipocytes are fat-containing cells that serve both to store energy in the form of triglycerides and to release free fatty acids for oxidation when energy is required. Adipose tissue is classified as white and brown. White adipose tissue stores energy in the form of triglycerides. The brown adipose tissue regulates body temperature by metabolism of lipids in response to cold. The adipocytes generate a wide variety of cytokines that have effects on lipid metabolism, blood pressure, inflammation, and appetite. Transcription factors that are important in metabolic control are also expressed in adipocytes. Another point of metabolic control are the peroxisome proliferation activated receptors (PPAR), which are nuclear receptors that control aspects of both triglyceride and glucose metabolism.7
Phenolic Compounds potential health Benefits and toxicity
Published in Quan V. Vuong, Utilisation of Bioactive Compounds from Agricultural and Food Waste, 2017
Deep Jyoti Bhuyan, Amrita Basu
Peroxisome proliferator-activated receptor gamma (PPAR-γ) has a vital role in glucose and fat metabolism. Thus, PPAR-γ agonists are widely used in the treatment of hyperglycemia, dyslipidaemia and their complications (Li et al. 2008). Phenolics with PPAR-γ ligand-binding activity have been obtained from licorice (Glycyrrhiza uralensis roots) which may help in the treatment of diabetes (Kuroda et al. 2003). Chronic sub-acute inflammation has also been accepted as an important factor in the development of insulin resistance and diabetes in animals and humans. Various nonflavonoid polyphenols have been shown to reduce the production of inflammatory mediators, such as IL-1β, IL-8, MCP-1, COX-2 or iNOS in these animal models of diabetes (Miranda et al. 2015).
Increasing cannabis use and importance as an environmental contaminant mixture and associated risks to exposed biota: A review
Published in Critical Reviews in Environmental Science and Technology, 2022
Emily K. C. Kennedy, Genevieve A. Perono, Dion B. Nemez, Alison C. Holloway, Philippe J. Thomas, Robert Letcher, Chris Marvin, Jorg Stetefeld, Jake Stout, Oliver Peters, Vince Palace, Gregg Tomy
There is evidence that cannabinoids may be capable of activating peroxisome proliferator activated receptors (PPAR), a superfamily of ligand-activated nuclear transcription factors that mediate the expression of genes involved in lipid metabolism, energy homeostasis, cell differentiation and inflammation (Morales & Reggio, 2017). Similar to CB1, PPARs can be found distributed throughout the CNS and PNS (Lu & Mackie, 2016; O’Sullivan, 2007). Moreover, as the PPAR superfamily closely senses local changes in lipids and are largely activated by fatty acids (Pertwee et al., 2010), lipophilic endocannabinoids and their analogues are able to serve as PPAR ligands and mediate transcription of PPAR-regulated gene targets (O’Sullivan, 2007; Pertwee et al., 2010). In fact, pharmacological inhibition of PPAR signaling via selective antagonism or genetic knock-out animal models demonstrate that cannabinoids can activate PPARs via direct binding, indirect binding or through its metabolites (O’Sullivan, 2007). Detailed reviews of other cannabinoid receptors and their pharmacology are reviewed elsewhere (Reviewed in: (O’Sullivan, 2016; Pertwee et al., 2010)).
Hepatic proteomic assessment of oral ingestion of titanium dioxide nano fiber (TDNF) in Sprague Dawley rats
Published in Journal of Environmental Science and Health, Part A, 2022
Worlanyo E. Gato, Ji Wu, Isaac Appiah, Olivia Smith, Haresh Rochani
Though, identification of individual proteins provides some insight into TDNF ingestion, grouping the proteins into aggregates and functional biological processes and functions will provide much clearer insight. Using DAVID bioinformatics tool,[19] individual proteins were grouped into associations referred to as gene ontology (GO) categories including functional biological process (BP), cellular components (CC) and molecular function (MF). GO categories included 325 biological processes, 140 molecular functions and 70 cellular components. The BP category showed oxidation reduction as the most represented. This was followed up by organic and carboxylic acid catabolism, response to drug, translation and response to extracellular stimulus. These processes are essential for the metabolic health of the cell. In the case of the molecular function categories, cofactor & coenzyme, lipid, nucleotide binding seemed to show the most appearance. Cellular components including the mitochondrion, cytosol, organelle envelope and membrane-enclosed lumen among others were highly represented in the gene ontology category. It appears that TDNF ingestion affects the metabolic acidity in the liver of Sprague Dawley rats. To further understand these protein associations via DAVID, pathway analysis was also performed. More than 30 pathways were affected by TDNF ingestion. Some of these were; drug metabolism, PPAR signaling pathway, and metabolism of xenobiotics by cytochrome p450. These pathways similar to the gene ontology categories, seem to play essential roles in metabolism within the liver. For instance the peroxisome proliferator-activated receptors (PPARs) are considered as nuclear receptor proteins that modulate transcription through the regulation of gene expression. [26]
The obesogen tributyltin induces features of polycystic ovary syndrome (PCOS): a review
Published in Journal of Toxicology and Environmental Health, Part B, 2018
Eduardo Merlo, Ian V. Silva, Rodolfo C. Cardoso, Jones B. Graceli
Tributyltin was found to promote elevated fat accumulation and obesity (Grün and Blumberg 2006; Janesick and Blumberg 2011). Obesogens, such as TBT, are known to induce obesity by increasing the number of fat cells (and fat storage into existing fat cells), changing the number of calories burned at rest, altering energy balance to favor storage of calories, and altering the mechanisms through which the body regulates appetite and satiety (Grün and Blumberg 2006; Janesick and Blumberg 2011). Thus, obesogens display the potential to disrupt multiple metabolic signaling pathways in the developing organism that might result in permanent changes in adult physiology (Grün and Blumberg 2006; Janesick and Blumberg 2012). Many of the TBT-initiated obesogenic effects (1–100 nM dose) are mediated through PPAR-γ, which acts as a key regulator of adipocyte differentiation and as a transcriptional regulator and/or effector of target genes, such as C/EBP (CCAAT/enhancer binding proteins), AFABP (adipocyte-specific fatty acid-binding protein), and FATP (fatty acid transport protein) (Carfi’ et al. 2008; Grün and Blumberg 2006). PPAR-γ is a member of the PPAR subfamily of nuclear hormone receptors expressed mainly in adipose and hepatic tissue. In addition to its role in the formation of new fat cells during early development, PPAR-γ modulates the function of adipocytes during adult life (Rosen et al. 2000) and is a critical gene involved in development of obesity in humans and rodents (Evans, Barish, and Wang 2004; Fajas et al. 1997; Grün and Blumberg 2006; Vidal-Puig et al. 1997). In fact, enhanced PPAR-γ signaling, attributed to a mutation that enhances its intrinsic activity, was found to be associated with human obesity (Ristow et al. 1998). Orio et al. (2003) suggested that a polymorphism in exon 6 of the PPAR-γ gene plays a role in development of obesity in PCOS patients.