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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.
Membrane Transport
Published in Lelio G. Colombetti, Biological Transport of Radiotracers, 2020
Membrane transport is in principle simple to measure. The transported molecule is incubated with a cell and the amount taken up after a certain time is measured. The rate-constant for influx or efflux can be related to the permeability the following way:
Inflammation
Published in George Feuer, Felix A. de la Iglesia, Molecular Biochemistry of Human Disease, 2020
George Feuer, Felix A. de la Iglesia
In advanced lesions, the cell membrane shows diverse structural distortions. A variety of conditions modify the permeability of the cell membrane and influence membrane transport, including disorders of water and electrolyte movements and specific transport defects for various substrates. These membrane lesions can be congenital or acquired. Acquired lesions are often derived from toxic interactions. Aminoaciduria is associated with defects in amino acid transport by the proximal tubular cells in the kidney.71 Lead toxicity can cause membrane transport defects.152 The erythrocyte membrane, especially, is very sensitive and shows cation transport defects in many disease conditions, such as various types of hemolytic anemias (sickle cell anemia, congenital hemolytic anemia), malaria, heavy metal poisoning, and digitalis poisoning. In cystic fibrosis and in syndromes related to bums, uremia, or shock, abnormalities of red cell transport have also been observed. In alcoholics, the so-called Zieve syndrome, plasma and erythrocyte membrane abnormalities are caused by changes in osmotic fragility due to abnormalities of membrane lipids.271 Neoplasmic transformations and virus infections are associated with chronic modifications of the cell surface properties.60,492
The role of SCAMP5 in central nervous system diseases
Published in Neurological Research, 2022
Ye Chen, Jiali Fan, Dongqiong Xiao, Xihong Li
In mammals, neurons, endocrine cells and exocrine cells all secrete proteins along the secretory pathway [17]. Genetics and in vitro experiments have revealed the molecular mechanism of exocytosis from neurons and from endocrine and exocrine cells. Innate immunity and adaptive immunity are regulated by cytokines, especially cytokines secreted by macrophages [18,19]. The membrane transport process during exocytosis and endocytosis is regulated by the SCAMP E peptide [20]. Previous studies on SCAMPs have mostly focused on the regulation of exocytosis during LDCV secretion or TGN vesicle transport. For example, SCAMP1 can promote the expansion and closure of fusion pores and participate in the regulation of LDCV secretion [21,22]. SCAMP2 interacts with phospholipase D1 and phosphatidylinositol diphosphate (PIP2) through its E peptide to regulate the formation of fusion pores during LDCV exocytosis [23].
Sacubitril-valsartan cocrystal revisited: role of polymer excipients in the formulation
Published in Expert Opinion on Drug Delivery, 2021
Yingxi Zhang, Xiaoxiao Du, Hanxun Wang, Zhonggui He, Hongzhuo Liu
Due to the variation of the cocrystal solubility in the pre-dissolved polymer, it was necessary to investigate the dissolution/solubility and permeability of cocrystals in the case of with/without pre-dissolution polymer from the D/P system. In the absence of polymer, SAC and VAL of cocrystal reached their maximum concentration (~15 mg/mL) in donor cells within the first 5 min and it maintained the concentrations throughout the experiment period. However, both individual SAC and individual VAL dissolved slowly and finally reached moderate concentrations, 9.79 mg/mL and 11.16 mg/mL, respectively. While physical mixtures led to inadequate dissolution as evidence of rather low concentrations of SAC and VAL in the donor side (Figure 3(a1, a3)). On the other hand, Figure 3(a2,a4) shows the permeability of API/cocrystals against time. It could be seen that the initial rate of permeability of cocrystals is no lower than that of individual API or physical mixture, but after 30 min, the permeation dropped significantly. A qualitative order of permeation might be stated as follows: individual API>physical mixture>cocrystal. Previous reports indicated that the driving force of membrane transport cannot be simplified to the concentration gradient dependent, especially in cases, where the solubility of API is altered [40]. The intermolecular hydrogen bonds between both of API might explain the drop of permeation in the case of cocrystals. The details will be discussed in the next section.
The effect of thermal therapy on the blood-brain barrier and blood-tumor barrier
Published in International Journal of Hyperthermia, 2020
Bhuvic Patel, Peter H. Yang, Albert H. Kim
A well-known characteristic of GBM is angiogenesis and neovascularization via a vascular endothelial growth factor (VEGF)-mediated mechanism that produces the immature, dilated, and leaky blood vessels of the blood-tumor barrier (BTB). In a mouse model of glioma, glioma cells displace the astrocyte end-feet from the endothelial surface, which in turn disrupts tight junctions and allows extravasation of various molecules from circulating blood into brain parenchyma [38]. Consistently, downregulation of critical BBB tight junction proteins such as claudin-1 and -5 has been found in human glioblastoma [39]. Aquaporins are membrane transport proteins that mediate water transport and play a key role in maintaining BBB integrity. Aquaporin-4 overexpression in astrocytes is believed to be a compensatory result of the loss of end-feet and increase in the volume of the perivascular space [40]. Moreover, as glioma cells infiltrate, they hijack the autoregulatory function of native astrocytes and independently mediate vascular tone [38]. The unique microenvironment created by the BTB, that of low oxygen tension and high interstitial pressure, is thought to contribute to selection of tumor cells with a more malignant phenotype [41].