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Regulation of Blood Glucose
Published in Robert B. Northrop, Endogenous and Exogenous Regulation and Control of Physiological Systems, 2020
The hormone glucagon (GLN), as previously discussed, is made by the pancreatic alpha cells of the islets of Langerhans. Its release rate is stimulated by low [BG]. Normal plasma concentration of glucagon is between 100 and 200 ng/1. One of the major effects of glucagon is to raise the rate at which glycogen is broken down, releasing glucose stored in the liver cells back into the blood and extracellular fluid. Glucagon also stimulates the process of gluconeogenesis, which also raises [BG] over the long term. The steps by which glucagon stimulates the breakdown of glycogen are well known.59 After combining with glucagon receptor proteins on the hepatic cell membrane, the enzyme adenyl cyclase is activated. Adenyl cyclase catalyzes the formation of cyclic AMP, which activates the following series of reactions: protein kinase regulator protein → protein kinase → phosphorylase b kinase → phosphorylase b → phosphorylase a. Phosphorylase a is the active enzyme that cleaves a glycogen unit, forming GIP. GIP is converted to G6P by another enzyme, and then phosphatase, activated by glucagon, removes the phosphate group and the resulting D-glucose diffuses out of the liver cell. Note that the outward flow of glucose occurs during periods of fasting as the glucose regulator attempts to maintain normoglycemia.
Preformulation of New Biological Entities
Published in Sandeep Nema, John D. Ludwig, Parenteral Medications, 2019
Riccardo Torosantucci, Vasco Filipe, Jonathan Kingsbury, Atul Saluja, Yatin Gokarn
Peptides can be linked to the mAb Fc domain, which extends the half-life of the peptide by invoking interaction with the neonatal Fc receptor (FcRN)-directed recycling pathway [31]. Alternatively, chemical conjugation to polyethylene glycol (PEG) – PEGylation - enables increased half-life by reducing renal clearance. An example is the peptide product peginesatide (Omontys®), approved for the treatment of anemia associated with chronic kidney disease. More recent concerns on the safety and tolerability of PEG-based injectable products have nonetheless led to the employment of different strategies [32,33] including linkage to albumin-binding small molecules or by the direct fusion of the peptide to albumin through protein engineering. In both scenarios, FcRn binding of the peptide is enhanced. The glucagon-like peptide-1 (GLP-1) agonist liraglutide (Victoza®) takes advantage of peptide’s acylation to bind albumin. Albiglutide (Tanzeum®), targeting the glucagon receptor, is a GLP-1 dimer fused to human albumin with a half-life of 6–7 days that importantly allows for once-weekly injections.
Molecular Aspects of the Activity and Inhibition of the FAD-Containing Monoamine Oxidases
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
Abnormal MAO activity has long been associated with neuro-pathology and behavioural changes (Finberg and Rabey, 2016). Humans with low MAO A activity and MAO A knockout mice display aggression (Bortolato and Shih, 2011). Low platelet MAO B is associated with alcoholism and behavioural disinhibition (van Amsterdam et al., 2006; Bortolato and Shih, 2011). Expression of MAO A and B differs by cell type and they are regulated differently. The upstream 30 base pair VTNR polymorphism in the MAO A promotor with 3 or 5 repeats results in as much as a 10-fold lower expression compared to the normal 4 repeats (Sabol et al., 1998), and a downstream VTNR has been reported to decrease expression of a novel isoform (Manca et al., 2018). Both MAO A and B have similar GC-rich promoter regions activated via Sp1 sites. Both promotors are down-regulated by the transcription factor R1 but MAO A expression is increased via the Glucagon Receptor Element and MAO B expression is increased by retinoic acid (Shih et al., 2011).
An efficient one-pot four-component Gewald reaction: Synthesis of substituted 2-aminothiophenes with coumarin–thiazole scaffolds under environmentally benign conditions
Published in Journal of Sulfur Chemistry, 2019
Kotthireddy Kavitha, Devulapally Srikrishna, Pramod Kumar Dubey, Pasula Aparna
In particular, among the thiophene derivatives, 2-aminothiophenes are versatile materials and have wide scope to apply in every branch of the science. Aminothiophenes have significant roles in exhibiting potent biological activities such as allosteric enhancers of adenosine receptor [18] and glucagon receptor antagonist [19]. Moreover, they found applications in the field of materials science, such as dyes [20], conductivity-based sensors [21], and biodiagnostics [22,23]. Generally, these substituted 2-aminothiophenes are prepared by Gewald reaction by a base-promoted one-pot three-component reaction between active methylene compound, sulfur and an aldehyde or a ketone [24,25]. The core structure is formed in the multicomponent reaction between a ketone or an aldehyde, an activated nitrile and sulfur. Since 1961 when the Gewald reaction was first reported, it became a universal method for the synthesis of substituted 2-aminothiophenes. But still, the research and generation of new compounds with this method is rapidly expanding due to its easy adaptability in the field of pharmaceutical and material chemistry. Although this one-pot synthesis is well established, a step-wise procedure which involves the preparation of α, β-unsaturated nitrile by the condensation of ketone or aldehyde with an activated nitrile, followed by base-promoted reaction with sulfur will provide the better understanding in reaction mechanism.