Radionuclide-based Diagnosis and Therapy of Prostate Cancer
Michael Ljungberg in Handbook of Nuclear Medicine and Molecular Imaging for Physicists, 2022
Amino acids are essential to cell metabolism and growth. Several amino acid transporter systems are overexpressed in PCa. Anti-1-amino-3-[18F]Flurocyclobutane-1-carboxylic acid (18F-fluciclovine-FACBC) is a non-naturally occurring amino acid, and its transport is primarily mediated by sodium-dependent amino acid transporters. Because the amino acid transporters that are most involved in 18F-fluciclovine transport mediate influx and efflux of amino acids, washout of the radiotracer occurs over time. The specificity of 18F-fluciclovine for PCa relies on altered metabolic pathways overexpressed in PCa. Studies have shown a detection rate of 40 per cent for patients with biochemical recurrence and a PSA level of 0.79 ng/mL or less. Direct comparison between 18F-fluciclovine and 11C-choline PET/CT has demonstrated overall superior imaging performance for 18F-fluciclovine in biochemically recurrent PCa. A good overview of 18F-Fluciclovine is found in Parent and Schuster and colleagues [71].
Peptidases and Peptides at the Blood-Brain Barrier
Gerard O’Cuinn in Metabolism of Brain Peptides, 2020
Vasopressin, a potent vasoconstrictor and modulator of blood-brain water transport (and substance P, a vasodilator peptide), bind to cerebral micro vessels via specific receptors. Their actions on vascular tone and on BBB permeability are mediated via activation of protein kinase C (PKC)72,95 suggesting that phosphorylation of specific substrate proteins may be involved. The effects of vasopressin on the affinity of leucine and phenylalanine for the large neutral amino acid transporter may be regulated by phosphorylation of the transporter.72 Arginine vasopressin (AVP) is reported to affect PKC after peripheral but not after central administration, suggesting that vasopressin receptors may be present only on the luminal membrane of the cerebral vasculature.72 AVP receptors at the BBB are of the VI type which mediate the contraction of smooth muscle. Binding of AVP to these receptors leads to a rapid increase in intracellular calcium in rat hippocampal endothelial cells.96 Vasopressin, like angiotensin II, is involved in the regulation of K+ transport across the BBB by inhibiting K+ channels via their action on G proteins.97
Dietary Influence on Muscle Protein Synthesis and Hypertrophy
Peter M. Tiidus, Rebecca E. K. MacPherson, Paul J. LeBlanc, Andrea R. Josse in The Routledge Handbook on Biochemistry of Exercise, 2020
AAs are fundamental in driving increased MPS via mTORC1 activity, though, again, determining the mechanisms through which AAs drive increased rates of MPS has been somewhat elusive. Increased circulating concentrations of AAs following digestion and absorption of protein are transported into skeletal muscle. The L-type amino acid transporter 1 (LAT1) plays a vital role in transporting AAs, mainly the branched-chain amino acid (BCAA) leucine, into skeletal muscle (57). Once inside the muscle, AAs influence mTORC1 activity via conversion of the Rag GTPases (Rag A/B and Rag C/D) to a nucleotide-bound state and association with the Ragulator complex, which subsequently binds directly to Raptor and facilitates the recruitment of mTORC1 to the lysosomal surface, increasing mTORC1 kinase activity. Conversely, the absence of AAs results in mTORC1 dissociating from the lysosomal membrane, preventing the essential interactions with co-activators (69). AAs also augment mTORC1 activity via human vacuolar protein sorting 34 (VPS34) and a calcium (Ca2+)/calmodulin (CaM)–dependent interaction (51). Building on these important discoveries, mTORC1 has been shown to “sense” AAs through two distinct mechanisms: vacuolar H+–adenosine triphosphatase ATPase (v-ATPase) (117) and GATOR 1–, GATOR 2–, and Sestrin2-mediated regulation (11, 25), both of which act via Rag GTPases and the Ragulator complex. Leucyl-tRNA synthetase (LeuRS) has been proposed as another candidate contributing to the AA sensing mechanism (61), though much work is still required to fully elucidate the AA-mediated mTORC1 activity.
Discovery of differentially expressed genes in the intestines of Pelteobagrus vachellii within a light/dark cycle
Published in Chronobiology International, 2020
Chuanjie Qin, Jiaxian Sun, Jun Wang, Yongwang Han, He Yang, Qingchao Shi, Yunyun Lv, Peng Hu
Moreover, a diurnal rhythmicity was noted for peptide absorption, for example, in nocturnal animals, the L-histidine absorption peak occurs during the dark phase(Furuya and Yugari 1974), which is coincident with higher expression levels of peptide transporter HPEPT1 (PEPT1) in the the dark compared with that in the light (Pan et al. 2002). In this study, b(0,+)-type amino acid transporter 1, sodium-coupled neutral amino acid transporter B, sodium-dependent neutral amino acid transporter 3, and excitatory amino acid transporter 1, all displayed upregulation at night, which contrasted with that of low affinity cationic amino acid transporter 2, a large neutral amino acids transporter. Excitatory amino acid transporter 1 is a sodium-dependent, high-affinity amino acid transporter that mediates the uptake of L-glutamate, L-aspartate, and D-aspartate (Arriza et al. 1994). The high-affinity transport of large neutral amino acids (e.g., phenylalanine, tyrosine, leucine, arginine, and tryptophan) is affected by sodium-independent, large neutral amino acids transporters. The peak time of mRNA expression was different for digestive enzymes and amino acid transporters within a light/dark cycle, which might suggest that the digestion and absorption of different amino acids was occurred at different times. Similarly, Senegalese sole (Solea senegalensis) showed their highest post-larval protein retention capacities when fed at nighttime (Marinho et al. 2014).
Emerging compounds and therapeutic strategies to treat infections from Trypanosoma brucei: an overhaul of the last 5-years patents
Published in Expert Opinion on Therapeutic Patents, 2023
Francesco Melfi, Simone Carradori, Cristina Campestre, Entela Haloci, Alessandra Ammazzalorso, Rossella Grande, Ilaria D’Agostino
Eflornithine (Figure 1) is recognized to be only efficacious against Tbg and can be safely associated with nifurtimox as a combination therapy. Eflornithine was first designed as an anticancer drug, and then it was repurposed for the treatment of late-stage HAT, because of its BBB permeability [11]. The drug correlates with racemic α-difluoromethyl-ornithine (DFMO) displaying a high structural analogy with ornithine. Indeed, it takes advantage of the amino acid transporter AAT6 to cross cell membrane easily [12]. The substrate ornithine is generally involved in the parasite polyamine biosynthetic pathway to produce spermidine, a component of trypanothione, the protozoan corresponding compound of mammalian glutathione. By hampering ODC, eflornithine can limit the crucial polyamine biosynthesis [13] and allow the accumulation of ornithine, S-adenosylmethionine, and decarboxylated S-adenosylmethionine, which finally block some methylation reactions of cellular macromolecules [14,15]. Surprisingly, eflornithine was found to counteract hirsutism in women, which was exploited as a repurposed therapeutic approach [16].
Ascorbate-conjugated nanoparticles for promoted oral delivery of therapeutic drugs via sodium-dependent vitamin C transporter 1 (SVCT1)
Published in Artificial Cells, Nanomedicine, and Biotechnology, 2018
Qiuhua Luo, Mingyan Jiang, Longfa Kou, Ling Zhang, Guyue Li, Qing Yao, Lei Shang, Ying Chen
Accordingly, a distinct advantage offered by particulate-based active targeting is establishing multivalent interactions with intestinal cells. Once achieved, multivalency can lead to enhanced avidity to target cells and can dramatically improve payload delivery [27,28]. Meanwhile, it is also important to note that achieving this effect is highly dependent on the surface density of ligands. An optimum contact between a carrier and a target on the biological surface is necessary to increase the drug absorption. In this study, an intermediate ascorbate modification density of 20% (w/w) was found to harvest the highest cellular uptake while an additional amount of ascorbate no longer contributed to the increase in the uptake. This was in accordance with our previous experimental results involving the transport characteristics of an amino acid transporter ATB0,+, suggesting that high ligand density was competing for transporters due to the multipoint interaction and was leading to a depletion of available transporters to fully wrap the NPs with a decrease in cellular endocytosis [17]. In addition, a large number of C6-labelled 20%As-PLGA NPs were found to congregate onto the cell membrane, by which the contact between NPs and enterocytes might be beneficial to the next biological process. These data might be interpreted as the fact that the selective moiety (As) was able to be recognized by the corresponding SVCT1 transporter on the cell membrane and to enter cells in the manner of SVCT1-mediated endocytosis.
Related Knowledge Centers
- Amino Acid
- Membrane Transport Protein
- Solute Carrier Family
- Apc Superfamily
- Aaap Family
- Haaap Family
- 6Tms Neutral Amino Acid Transporter Family
- Basic Amino Acid Antiporter Family
- Putative Amino Acid Permease Family
- Glutamate Transporter