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Lysosomal Ion Channels and Human Diseases
Published in Tian-Le Xu, Long-Jun Wu, Nonclassical Ion Channels in the Nervous System, 2021
Peng Huang, Mengnan Xu, Yi Wu, Xian-Ping Dong
Compared with mitochondria and ERs, lysosomes only occupy a small fraction of the intracellular space in many cell types (Alberts et al., 2014; Holtzman, 1989; Luzio et al., 2007; Xu and Ren, 2015). However, they play an essential role in cell functions by altering their position, number, size, composition, activity, and interaction with other organelles upon environmental changes. Like the PM, the lysosomal membrane also contains many ion channels that control almost all lysosomal functions. However, our knowledge about lysosomal ion channels is still sparse. Currently, only eight proteins have been definitely established as lysosomal ion channels. These ion channels not only regulate the intralysosomal environment to meet specific needs such as lysosomal degradation and membrane trafficking in the endocytic, phagocytic, and autophagic pathways but also control the cytosolic environment to activate a variety of intracellular signaling pathways such as Ca2+ signaling and nutrient sensing pathways, thereby maintaining cellular homeostasis. Despite some progress in our understanding of lysosomal ion channels, many questions remain to be addressed in more detail. For example, how are they regulated by environmental factors and cellular cues? How do they regulate cell functions and organellular homeostasis? Do they function in lysosome-related organelles in specialized cells, and if so how? Do they contribute to the communication of lysosomes with other cellular structures and if so how? How are they involved in human diseases?
Small Bowel Injury by Ethanol
Published in Victor R. Preedy, Ronald R. Watson, Alcohol and the Gastrointestinal Tract, 2017
The glucose and other "nonelectrolyte"* carriers of the BBM have high affinity to nonelectrolytes in the presence of high Na+ and low K+ concentration and low affinity (i.e., release glucose or other nonelectrolytes), when K* concentration is high and Na+ concentration is low. The driving force of the transport of glucose and other nonelectrolytes by carrier systems across the BBM into the cell is the Na+ and K+ gradient between the high Na+ and low K+ concentration of the luminal fluid and the low Na+ and high K+ concentration inside the cell. This gradient is maintained by the Na+, K+ ATPase (the sodium pump) of the BLM which actively transports sodium out of the epithelial cell into the LIS and K+ from LIS to the cell. Glucose traverses the intracellular space where it is partially utilized for epithelial cell metabolism. Glucose that has not been metabolized is extruded at the BLM by a nonsodium dependent carrier.174
Raised Intracranial Pressure
Published in John W. Scadding, Nicholas A. Losseff, Clinical Neurology, 2011
In an adult, the normal composition is approximately 87 per cent brain parenchyma, 9 per cent CSF, 4 per cent blood. The brain parenchyma can be further divided into an intracellular and an extracellular compartment. The typical adult intracranial volume of 1500 mL consists of about 1100 mL intracellular space, 200 mL extracellular space, 140 mL of CSF and 60 mL of blood.
Targeting the undruggable: emerging technologies in antibody delivery against intracellular targets
Published in Expert Opinion on Drug Delivery, 2020
Suchada Niamsuphap, Christian Fercher, Sumukh Kumble, Pie Huda, Stephen M Mahler, Christopher B Howard
The criteria for selecting a suitable therapeutic target have been discussed widely in the literature [4–6], particularly when dealing with conditions such as cancer, inflammation, and autoimmunity. In an ideal situation, the diseased tissue expresses antigen markers exclusively in relation to other healthy tissues. However, in most cases, this is far from reality, as diseased tissue will only express antigen markers at increased levels compared to their healthy counterparts, which can nonetheless serve as an attractive target. The second most important criterion in selecting a suitable target is its localization, which in virtue of current biopharmaceutical interventions, is either the cell membrane or the extracellular space. This allows antibodies or other biologics to access the target. A classic example is the expression and localization of the epidermal growth factor receptor (EGFR) [7] which is widely targeted for the treatment of many cancers, including colorectal cancer [8]. In contrast, there are various molecular activities occurring within the intracellular space that contributes to the pathology of otherwise healthy tissues and such proteins are equally attractive for biopharmaceutical development. The main obstacle when targeting these proteins is the inaccessibility of the intracellular space given the nature of the cell membrane, making the delivery of polypeptides to the intracellular space to target proteins, such as transcription factors, a new and challenging avenue in disease management.
Development of new agents for peripheral T-cell lymphoma
Published in Expert Opinion on Biological Therapy, 2019
Yuta Ito, Shinichi Makita, Kensei Tobinai
Pralatrexate (10-propargyl-10-deazaaminopterin) is an anti-folate agent that inhibits dihydrofolate reductase (DHFR). As DHFR is a key enzyme in the conversion of dihydrofolate to tetrahydrofolate, which is required for the synthesis of thymidylate and purine nucleotides, the inhibition of DHFR blocks cell division in the S phase [7]. Compared with other anti-folate agents, such as methotrexate, high intracellular concentrations of pralatrexate can be reached owing to its high affinity for the reduced folate carrier-1 (RFC-1) that takes pralatrexate into intracellular space. This higher affinity for RFC-1 may be associated with the greater selectivity of pralatrexate for tumor cells because many tumors overexpress RFC-1. Furthermore, intracellular pralatrexate is metabolized into a polyglutamated form by folylpolyglutamate synthetase; polyglutamates are preferentially retained in the intracellular space, which makes them less susceptible to efflux-based drug resistance [8].
Enhanced anti-proliferative efficacy of epothilone B loaded with Escherichia coli Nissle 1917 bacterial ghosts on the HeLa cells by mitochondrial pathway of apoptosis
Published in Drug Development and Industrial Pharmacy, 2018
Wenxing Zhu, Lujiang Hao, Xinli Liu, Orlando Borrás-Hidalgo, Yuyu Zhang
Recently, bacteria ghosts (BGs) have been widely concerned as novel drug delivery vehicles [11,12]. BGs are empty non-denatured bacterial envelopes of Gram-negative bacteria which are produced by the controlled expression of bacteriophage PhiX174 lysis gene E [13]. They are devoid of any cytoplasmic content so the carrier capacity of the inner cytoplasmic lumen provides an intracellular space of approximately 250 femtoliter per BG. Thus, the BGs retain natural outer surface make-ups which provide them with excellent immunogenicity, bioadhesive characters, and the original targeting functions of the derived bacteria. They might be effectively recognized and taken up by antigen representing cells and targeted to specific tissues or cancer cells [14]. Moreover, the safety and relatively low production cost of BGs offer a significant technical advantage as a good candidate of drug delivery vehicles. Noteworthy, BGs produced from Mannheimia haemolytica were used for the in vitro delivery of the moderate hydrophilic cytostatic drug doxorubicin (DOX) to human colorectal adenocarcinoma (Caco-2) cells, the loaded DOX was released within the cells and exhibited potent anti-proliferative properties on the cells [15].