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Finding a Target
Published in Nathan Keighley, Miraculous Medicines and the Chemistry of Drug Design, 2020
Transport across plasma membranes is a crucial part of a cells existence. The cell membrane presents a barrier to most polar molecules, which is important for maintaining concentrations of solutes in the cytoplasm. Likewise, the membrane-bound organelles within the cell can have a specific concentration of molecules contained within; different from that of the cytoplasm or extracellular medium. However, critical substances required by the cell must have a means of entering the cell as well as the removal of waste products. This is where the key role of transmembrane transport protein comes into fruition; as they are responsible for transporting these water-soluble molecules across the plasma membrane. A given transport protein will be responsible for assisting the movement of closely related groups of organic molecule, or a specific ion, across the membrane. There are two classes of membrane transport protein: carrier proteins and channel proteins. Carrier proteins have moving parts, activated by the chemical energy source ATP, that mechanically move small molecule across the membrane. This is known as active transport. Channel proteins form a narrow hydrophilic pore that enables the passive movement of inorganic ions, known as facilitated diffusion. By these mechanisms, the cell can create large differences in composition between the internal environment and extracellular medium. This is essential for specialised cells to perform their role in the body.
The cell
Published in Laurie K. McCorry, Martin M. Zdanowicz, Cynthia Y. Gonnella, Essentials of Human Physiology and Pathophysiology for Pharmacy and Allied Health, 2019
Laurie K. McCorry, Martin M. Zdanowicz, Cynthia Y. Gonnella
In the process of mediated transport, carrier proteins embedded within the plasma membrane assist in the transport of larger, polar molecules into or out of the cell. When a substance attaches to a specific binding site on the carrier protein, the protein undergoes a conformational change such that this site with the bound substance moves from one side of the plasma membrane to the other. The substance is then released.
Imaging of Intracellular Targets
Published in George C. Kagadis, Nancy L. Ford, Dimitrios N. Karnabatidis, George K. Loudos, Handbook of Small Animal Imaging, 2018
In order to cross the hydrophobic interior of the cell membrane, hydrophilic and large molecules need the help of membrane transport proteins. These integral membrane proteins provide a continuous protein-lined pathway through the bilayer. Two major classes can be distinguished: channel proteins, which form a narrow pore through which ions can pass (passive transport), and carrier proteins, which translocate specific molecules across (passive or active transport). However, these transport mechanisms are less relevant to imaging of intracellular targets. Indeed, ion channels are important in muscle and neuronal excitation, and a well-known example of a carrier protein that carries out passive transport is the glucose transporter, exploited by the most used extracellular molecular imaging marker [18F]-FDG. Active transporters include ATP-driven ion pumps, coupled transporters (or secondary active transporters), and ABC transporters. This final type of transporter is specialized in pumping small molecules, including drugs and other toxins, out of the cells and is not only involved in multidrug resistance in cancers but also contributes to the blood-brain barrier.
Thyroid Feedback Quantile-based Index correlates strongly to renal function in euthyroid individuals
Published in Annals of Medicine, 2021
Sijue Yang, Shuiqing Lai, Zixiao Wang, Aihua Liu, Wei Wang, Haixia Guan
The secretion of thyroid hormone is regulated by hypothalamic-pituitary-thyroid (HPT) axis. Thyrotropin-releasing hormone (TRH) from the hypothalamus promotes the synthesis and release of TSH from the anterior pituitary, which plays an important role in all stages related to the production and secretion of thyroid hormones from the thyroid gland. The levels of TRH and TSH are in turn modulated by the negative feedback of thyroid hormones. Thyroid hormones are mainly secreted in the form of T4, which is catalyzed by deiodinases to form the bioactive T3. Both will bind to carrier proteins in the circulation and enter cells via membrane transporters. T3 then further binds to the nuclear thyroid hormone receptors. Therefore, thyroid function is regulated by the HPT axis and other factors associated with thyroid hormone conversion and bioactivity [26].
Influences of different sugar ligands on targeted delivery of liposomes
Published in Journal of Drug Targeting, 2020
Changmei Zhang, Zhong Chen, Wenhua Li, Xiaoying Liu, Shukun Tang, Lei Jiang, Minghui Li, Haisheng Peng, Mingming Lian
The movement of glucose in the blood or tissue is mediated by facilitative Glucose Transporter (GLUT) on cell membrane. GLUT is a kind of carrier protein embedded on the cell membrane. It transports glucose along the concentration gradient by using a way of facilitated diffusion without consuming energy. Therefore, GLUT can be specifically identified and bound by glucose or glycoconjugate [3]. The specific substrates of GLUT include glucose, galactose, mannose and their derivatives. These substrates can be modified relevant ligand complexes, which will occur cluster and invagination, then be swallowed by cells into lysosomes to release the drug at last [4]. Therefore, conjugation of some different ligands on the surface of liposome can achieve the purpose of active targeted drug delivery and improve the therapeutic effect of drugs.
Evaluating the safety profile of focused ultrasound and microbubble-mediated treatments to increase blood-brain barrier permeability
Published in Expert Opinion on Drug Delivery, 2019
Dallan McMahon, Charissa Poon, Kullervo Hynynen
Drug delivery to the brain is limited by the BBB. Gaseous or small hydrophobic molecules (<400 Da) can diffuse across the BBB; however, more than 98% of the small-molecule drugs are excluded from entry into the brain parenchyma [1]. A major constituent of the BBB that limits entry of substances into the brain is the presence of tight junction proteins between endothelial cells, contributing to the physical barrier between the systemic circulation and brain [2]. Astrocytic endfeet processes, which enwrap almost all brain capillaries [3], as well as pericytes [4] and the anionic extracellular matrix also act to limit drug penetration and diffusion into the CNS [5,6]. Carrier proteins allow the transport of specific molecules into and out of the brain parenchyma, such as glucose and neutral amino acids [7]. The BBB limits exposure of the brain parenchyma to pathogens and aids in the maintenance of homeostasis, ensuring optimal conditions for neural function (Figure 1).