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Antimonial Agents
Published in M. Lindsay Grayson, Sara E. Cosgrove, Suzanne M. Crowe, M. Lindsay Grayson, William Hope, James S. McCarthy, John Mills, Johan W. Mouton, David L. Paterson, Kucers’ The Use of Antibiotics, 2017
Aquaglyceroporins (AQPs) are known to transport trivalent metalloids. Aquaglyceroporin 1 (AQP1) has been identified in Leishmania and has been shown to mediate uptake of Sb3+ into the parasite (Gourbal et al., 2004). Once inside the parasite, the primary target is believed to be a specific thiol redox pathway. Trypanothione synthetase and trypanothione reductase are components of thiol pathway metabolism in Leishmania, a pathway common to all parasites of the Trypanosomatidae family but absent in the mammalian host (Baiocco et al., 2009). Trypanothione reductase maintains the main thiols in Leishmania parasite, especially trypanothione, in a reduced state. Trypanothione, possibly in conjunction with thiol-dependent reductase-1, promotes reduction of Sb5+ to Sb3+ (Denton et al., 2004). Trivalent antimony then binds with high affinity to the active site of TR, profoundly inhibiting the thiol reduction potential of the cell (Baiocco et al., 2009). This exposes the parasite to oxidative stress by the reactive oxidative species produced by the host macrophage and facilitates killing of the parasite (Baiocco et al., 2009). A separate target of Sb3+ may be zinc finger proteins involved in DNA repair, leading to DNA fragmentation and ultimately apoptosis (Frezard et al., 2009).
Aquaporin-Mediated Water Transport in Intrahepatic Bile Duct Epithelial Cells
Published in Gianfranco Alpini, Domenico Alvaro, Marco Marzioni, Gene LeSage, Nicholas LaRusso, The Pathophysiology of Biliary Epithelia, 2020
Anatoliy I. Masyuk, Nicholas F. LaRusso
AQPs are divided into 2 main groups (i.e., orthodox and multifunctional AQPs) based on their abilities to transport nonionic small molecules such as urea and glycerol in addition to water.3,4 The orthodox AQPs (i.e., AQPO, AQP1, AQP2, AQP4, AQP5, AQP6, and AQP8) are water-selective.3,10 Multifunctional aquaporins (i.e., AQP3, AQP7, and AQP9), recently termed aquaglyceroporins, are permeable to water, urea, and glycerol.3,4 Moreover, it is evident now that transport properties of AQPs are even more diverse. For instance, AQP1 functions as a water channel, but may also be permeable to CO2.18,19 It has also been shown that AQP1 not only mediates the flux of water when expressed in Xenopus oocytes but also serves as a cGMP-gated ion channel.20,21 However, the passage of CO2 and ions through AQP1 is a controversial issue.22–24 Recent studies have shown that only an extremely small subpopulation of AQP1 molecules reconstituted into planar lipid bilayers may behave as ion channels (i.e., the number of ion channels is more than 1 million-fold lower than the number of water channels).25 A small degree of permeation by glycerol has also been seen in Xenopus oocytes expressing AQP1 .10 AQP6 is functionally distinct from other known AQPs. When expressed in Xenopus oocytes, AQP6 exhibits low, but significant, basal water permeability; however, when treated with the water channel inhibitor, HgCl2, the water permeability of AQP6 oocytes rapidly rises up to 10-fold and is accompanied by ion conductance.26,27 Rat AQP8 transports water, but mouse AQP8 is permeable to both water and urea.28–30 AQP9 is able to transport glycerol, urea, carbamides, polyols, purines, and pyrimidines in addition to water. 31–33 AQP 10 is a water-selective channel despite its high sequence homology to aquaglyceroporins.34
Modulation of Lipid Biosynthesis by Stress in Diatoms
Published in Gokare A. Ravishankar, Ranga Rao Ambati, Handbook of Algal Technologies and Phytochemicals, 2019
Bing Huang, Virginie Mimouni, Annick Morant-Manceau, Justine Marchand, Lionel Ulmann, Benoit Schoefs
Arsenic is a metalloid released by human activities and can be found in fresh and marine water (Wang et al., 2015). In microalgae, arsenic compounds are found in cytosolic and membrane fractions, as inorganic arsenic species such as arsenite and arsenate or as different forms such as arsenobetaine, arsenocholine, arsenosugars and in lipid-soluble fractions as arsenolipids (Duncan et al., 2013). These molecular species are less toxic than inorganic ones (Hsieh and Jiang, 2012) except for arsenolipids (Meyer et al., 2014). The accumulation of organoarsenical compounds in microalgae is accomplished by the phosphate transport system, aquaglyceroporins and hexoses permeases (Wang et al., 2015). At the cellular level, arsenate competes with phosphate in phosphorylation and oxidative phosphorylation reactions (Fujiwara et al., 2000), generates an oxidative stress and participates in division inhibition (Levy et al., 2009). Arsenite interferes with protein synthesis leading to membrane degradation and cell death (Wang et al., 2015). Arsenate competing with phosphate in microalgal metabolism has been tested in the diatom P. tricornutum and Thalassiosira pseudonana. Arsenic was found in several cell fractions, including the lipid one (Duncan et al., 2013). The dominant arsenic species contained in the lipid-soluble fraction were sulfate-, glycerol- and phosphate arsenoribosides with 50 to 80% of the total arsenic of this fraction. Arsenoribosides are considered as the final As species in microalgae (Edmonds and Francesconi, 2003). Because arsenoriboside-containing phospholipid has been identified (García-Salgado et al., 2012), it has been proposed that this species could be the product of arsenolipid hydrolysis present in the lipid-soluble fraction (Duncan et al., 2013). Few studies have been dedicated to the toxicological effect of arsenic on diatoms. In rice, arsenite and silica share the same transport system (Seyfferth and Fendorf, 2012). Silica being a major nutrient in diatoms, it has been hypothesized that silica and As could also be co-transported in diatoms (Ding et al., 2017). In natural waters, mixed arsenic species such as arsenite or arsenate but also organoarsenicals such as monomethylarsenate or dimethylarsenate co-exist (Hellweger et al., 2003), allowing a place for combined or interactive effects between As forms. In the diatom Nitzschia palea, a higher toxicity of arsenite and dimethylarsenate than when individually u sed has been reported.
Drugs and nanoformulations for the management of Leishmania infection: a patent and literature review (2015-2022)
Published in Expert Opinion on Therapeutic Patents, 2023
Mariana Verdan, Igor Taveira, Flávia Lima, Fernanda Abreu, Dirlei Nico
Chemotherapy against leishmaniasis is the principal way to combat the disease. Therefore, failures in treatment are incredibly worrying. One of the worst scenarios of resistance to antileishmanial drugs is found in India, where a high number of cases of VL, almost 100%, are resistant to treatment with pentavalent antimonials [79]. These absurd levels of resistance to pentavalent antimonials are probably related to the expression of ABC-type transporters close to the parasite’s flagellar pocket [80]. It is also worth mentioning the important role of aquaglyceroporins [81] and high levels of trypanothione and tryparedoxin peroxidase in clinical isolates [82]. Due to the long duration of the treatment and the high toxicity, the patient gives up the treatment and does not complete the necessary cycle for the success of the treatment. This also contributes to the emergence of treatment failures and drug resistance.
An overview of carbonic anhydrases and membrane channels of synoviocytes in inflamed joints
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2019
The aquaporins (AQPs) are water or small molecule-transporting channel proteins across the plasma membranes of various human tissues and cell types37. Thirteen types of AQPs (AQP0–AQP12) from mammalian tissues have been cloned and sequenced38. The AQPs are classified into two groups: water selective channel (orthodox AQPs) and water, glycerol, nitrate (AQP6), and urea channel (aquaglyceroporins; AQP 3, AQP7, and AQP9)39. The permeability of AQPs is dependent on osmotic and hydrostatic gradients and pH values. Several investigations have shown the involvement of AQPs in cartilage damage in joint diseases like RA and osteoarthritis (OA). AQP1 is distributed in the articular cartilage and the synovium40. AQP1 is also expressed in chondrocytes and synoviocytes of RA patients41. Up-regulated AQP1 found in the inflamed synovial tissues of RA patients might play a potential pathological role in hydrarthrosis and joint swelling42. Acetazolamide, AQP1 inhibitor, was decreased AQP1 protein level via inhibition of NF-κB activation and subsequent reduction of hind pow swelling in adjuvant-induced arthritis rats, suggesting that attenuation of AQP1 mediates anti-arthritis effect42. It is well-known that AQP4 possesses high water permeability than that of AQP143 and its role in the nervous system has been studied44. AQP4 is over-activated in rat articular chondrocytes and high homologues of AQP4 between rat and human45; however, the pathological role of AQP4 in RA is still unclear. AQP9 was strongly induced upon treatment with TNF-α in FLS and was also expressed in the RA and OA synovial tissues41. Although the pathological roles of AQP in the synovial tissues remain to be elucidated, experimental evidence has revealed that AQPs are involved in the pathogenesis of hydrarthrosis and synovitis (Table 1).
Metal-metal interaction and metal toxicity: a comparison between mammalian and D. melanogaster
Published in Xenobiotica, 2021
Xiaoyu Yu, Xianhan Tian, Yiwen Wang, Chunfeng Zhu
In addition to the above common mechanisms, toxic metals can also be transported through other specific channels or proteins. Al can replace Ca2+ and Mg2+ in citrate, then the Al-citrate complexes are transported by monocarboxylate transporter 6 (MCT6) or sodium-independent glutamate transporter family Xc− (Yokel et al.2002, Dai et al.2015). Pb2+ and Cd2+, as Ca2+ analogs, can competitively transport through Ca2+-ATPase transporters in Ca2+ absorption channels (Simons 1988, Bressler et al.2004). Among essential metals, Mn2+, Zn2+, and Fe2+ can also be transported by the Ca2+ absorption channel. The uptake of methylmercury (MeHg) is mainly through L-neutral amino acid and peptide transport system as MeHg-S-Cys complex, while the excretion is mediated by multidrug resistance-associated protein2 (MRP2), a member of the ABC multidrug resistance transporter family (Aschner et al.2010, Farina et al.2011). Uptake of Cr6+ is mediated by anion channels such as SO42– and HPO42– channels (Chandra et al.2016). As3+ can penetrate the cell membrane through the aquaglyceroporins (AQPs) which are used to transport small molecules such as water and glycerol (Leung et al.2007, Shinkai et al.2009). Besides, glucose transporter isoform 1 (GLUT1), a glucose permeability enzyme, is also involved in the uptake of As3+ and MMA (III) (Vannucci et al.1997, Liu et al.2006). Subsequently, intracellular glutathione mediates As detoxification by forming a complex with As, which can be secreted by multidrug resistance-associated protein1 (MRP1) (Leslie et al.2004). There is no evidence of direct transporter for Cd excretion from cells, but studies in D. melanogaster suggest that the ATP-dependent membrane protein p-glycoprotein (p-gp) and ABC transporter DmHMT-1 may be associated with Cd tolerance in D. melanogaster (Callaghan and Denny 2002, Sooksa-Nguan et al.2009).