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An Overview of the Biological Actions and Neuroendocrine Regulation of Growth Hormone
Published in George H. Gass, Harold M. Kaplan, Handbook of Endocrinology, 2020
Growth hormone promotes protein synthesis, as indicated by decreased excretion of nitrogen subsequent to growth hormone administration. More specifically, early studies by Noall et al.63 were able to show that growth hormone can stimulate amino acid transfer from the extracellular to the intracellular compartment utilizing the nonmetabolizable amino acid, 14C-α-aminoisobutyric acid (14C-AIB). Extending this observation, Riggs and Walker64 reported that hypophysectomy diminishes the incorporation of 14C-AIB into muscle, and this effect can be reversed by the administration of bovine growth hormone.
Acetylcholine
Published in Geoffrey Burnstock, Susan G. Griffith, Nonadrenergic Innervation of Blood Vessels, 2019
Certainly one of the most well-developed vascular barrier systems is the blood-brain barrier.93 Interestingly, this vascular bed is well documented to synthesize and store acetylcholine, although the function of acetylcholine remains in question.9 By analogy with the primate placenta, where inhibition of choline acetyltransferase activity decreases amino acid transport,35 it has been hypothesized that acetylcholine synthesis in the cerebral circulation is related to blood-brain barrier transport.40 This hypothesis was tested using a model system, the ability of cerebral arteries to accumulate α-aminoisobutyric acid in vitro by a ouabain-sensitive, so-called A system, transport mechanism.94, 95 Indeed, inhibition of choline acetyltransferase activity by (2-benzoylethyl) trimethylammonium chloride also decreased the ouabain-sensitive accumulation of α-aminoisobutyric acid into cerebral arteries. These findings suggest that synthesis of acetylcholine may be important in regulation of blood-brain barrier activity, underscoring the importance of considering alternative roles for vascular cholinergic systems.
Prospective Therapeutic Applications of Bacteriocins as Anticancer Agents
Published in Ananda M. Chakrabarty, Arsénio M. Fialho, Microbial Infections and Cancer Therapy, 2019
Lígia F. Coelho, Nuno Bernardes, Arsénio M. Fialho
Class I bacteriocins, the lantibiotics, are small (<5 kDa), heat-stable peptides that enclose a high occurrence of post-translational modifications. These peptides contain characteristic polycyclic thioether aminoacids, such as lanthionine and methyllanthionine, and unsaturated aminoacids, such as dehydroalanine and 2-aminoisobutyric acid [54]. Lantibiotics are encoded by the structural genes lanA (the abbreviation lan is used for homologous genes of different lantibiotic gene clusters) and produced as prepeptides consisting of an N-terminal leader peptide and a C-terminal propeptide part. Together with lan genes paraphernalia regarding proteolysis and modification, they form biosynthetic gene clusters with several transcription units that can be located either on the chromosome or on mobile elements such as plasmids or transposons [56].
Recent advances in proteolytic stability for peptide, protein, and antibody drug discovery
Published in Expert Opinion on Drug Discovery, 2021
Xianyin Lai, Jason Tang, Mohamed E.H. ElSayed
2-Aminoisobutyric acid (Aib, α-aminoisobutyric acid, α-methylalanine, or 2-methylalanine) is a commonly used non-proteinogenic amino acid to replace cleavage site amino acids. Due to the cleavage between positions 2 and 3 by DPP4, native GLP-1 has a very short half-life. Besides, A2G was used in the engineering of exenatide, A2Aib was used to engineer albiglutide, albenatide, lixisenatide, traspoglutide, and semaglutide to eliminate the cleavage by DPP4. Taspoglutide showed outstanding resistance to DPP4 and half-life of 13 h in human plasma upon subcutaneous administration without an acyl chain to bind albumin [104]. Semaglutide containing a fatty acid chain connected to Lys26 through a miniPEG spacer achieved a half-life of 6–7 d in plasma, enabling a once-weekly subcutaneous administration [105].
Novel approaches to pharmacological management of type 2 diabetes in Japan
Published in Expert Opinion on Pharmacotherapy, 2021
Semaglutide is one of the six injectable GLP-1 R agonist preparations available in Japan. It has 94% homology to human GLP-1 in terms of its amino acid sequence. Alanine at residue 8 was replaced with 2-aminoisobutyric acid to improve peptide stability by protecting it against DPP-4 enzymatic activity. In addition, C18 fatty acids were conjugated to a lysine at residue 26 via a macromolecular hydrophilic linker and γ-glutamic acid (acylation) to reinforce binding of the peptide to albumin, which resulted in delayed degradation and reduced renal clearance. Furthermore, lysing at residue 34 lysine has been replaced with arginine to inhibit the binding of C18 fatty acids. In this manner, the half-life of the peptide in the blood has been extended to approximately 1 week. This compound, which has a low molecular weight, can regulate, among others, nerve cells expressing the GLP-1 R in the arcuate nucleus of the hypothalamus, where the blood‒brain barrier is absent [50]. In a subgroup analysis of Japanese patients, weekly subcutaneous treatment with 1 mg of semaglutide for 30 weeks reduced HbAlc by 2% or more, accompanied by weight loss of 5% or more in over 50% of all patients, and weight loss of 10% or more in over 20% of patients [16]. In a clinical study, semaglutide injection was well tolerated in Japanese T2DM patients. Gastrointestinal adverse events, which mostly involved mild and transient nausea or constipation, occurred in a dose-dependent manner.
Adhesion molecule L1 inhibition increases infarct size in cerebral ischemia-reperfusion without change in blood-brain barrier disruption
Published in Neurological Research, 2021
Oak Z. Chi, Thomas Theis, Suneel Kumar, Antonio Chiricolo, Xia Liu, Saad Farooq, Nishta Trivedi, Wise Young, Melitta Schachner, Harvey R. Weiss
After one hour of MCAO and 2 hours of reperfusion, 20 μCi of 14C-α-aminoisobutyric acid (14C-AIB) (molecular weight 104 Da, Amersham, Arlington Heights, Illinois) was injected intravenously and flushed with 0.5 mL of saline. Blood samples were collected from the femoral arterial catheter at 20 sec intervals for the first 2 min and then every min for the next 8 min. Five min after injecting 14C-AIB, 20 μCi of 3H-dextran (molecular weight 70,000 Da, Amersham, Arlington Heights, IL) was injected intravenously and flushed with 0.5 mL saline. After collecting the ten-min arterial blood sample, the animals were decapitated, and their brains immediately frozen in liquid nitrogen. The following brain regions were dissected: IC, CC, IH, CH, CBLL, and pons. Brain samples were solubilized in SolueneTM (Packard, Downers Grove, IL). Arterial blood samples were centrifuged, and the plasma was separated. Plasma and brain samples were counted on a liquid scintillation counter that was equipped for dual label counting. Quench curves were prepared using carbon tetrachloride. All samples were automatically corrected for quenching. The blood-brain transfer coefficient for 14C-AIB was determined assuming a unidirectional transfer of 14C-AIB over a 10-min period of the experiment using the following equation as described previously [26,27]: