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Measuring Oxidative Damage and Redox Signalling
Published in James N. Cobley, Gareth W. Davison, Oxidative Eustress in Exercise Physiology, 2022
James N. Cobley, Gareth W. Davison
Key interpretational points are threefold. First, the absolute steady state of a biomarker is in dynamic equilibrium with formation and repair mechanisms (Murphy et al., 2011). A change could simply reflect differential repair (Cobley et al., 2017), as opposed to increased damage, especially if repair consumes ATP. For example, exercise-induced ATP demand could deprive sulphiredoxin of the ATP needed to reverse sulphinic (SO2) acid oxidation, which could lead to some proteins becoming irrevocably inactivated (Akter et al., 2018). Likewise, any change at the tissue or systemic level could simply reflect differential efflux. Second, far from being inert end-points, many oxidative macromolecule adducts are bioactive (Niki, 2012). For example, 4-HNE, a lipid peroxidation metabolite, can oxidise protein thiols by Michael addition or Schiff base formation, which could enact redox signalling (Zhang and Forman, 2017). Oxidative damage and redox signalling can, therefore, interact (Cobley et al., 2015a, b; Margaritelis et al., 2016a, b). Third, without functional annotation or appropriate reporters (e.g., enzyme assays ideally with and without selective removal of the modification), it is difficult to infer the biological meaning of any oxidative damage observed. Without corroborating evidence, it is unwise to conclude, especially from a single surrogate, that exercise-induced oxidative damage is functionally significant.
Lipopolysaccharide and the Permeability of the Bacterial Outer Membrane
Published in Helmut Brade, Steven M. Opal, Stefanie N. Vogel, David C. Morrison, Endotoxin in Health and Disease, 2020
Even though the intact OM with no genetic defects in LPS deep core and lipid A synthesis plays the key role in the resistance of enteric bacteria to hydrophobic inhibitors, it can ultimately only retard the diffusion of those drugs through the OM. Bacteria additionally need energy-dependent mechanisms to pump hydrophobic solutes, diffused into the cytoplasm, out from the cell. Such efflux mechanisms have recently been a subject of intensive research. The AcrAB and EmrAB efflux systems have been discovered and characterized (45–48). The acrA mutants were reported in 1968 as supersusceptible to acriflavine and thereafter intensively studied, but the underlying defect in them was only identified 25 years later. It is probable that also some other previously partially characterized, antibiotic supersusceptible enterobacterial mutants such as the SSB mutant of S. typhimurium (49) will eventually prove to be efflux mutants.
Pseudomonas aeruginosa
Published in Firza Alexander Gronthoud, Practical Clinical Microbiology and Infectious Diseases, 2020
Reduced permeability Reduced permeability is caused by several mechanisms, which affect all classes of antibiotics including polymyxins.Of note, porin oprD mutations affect imipenem. This mutation is often associated with overexpression of efflux system. Imipenem can thus trigger resistance to other classes of antibiotics.
Efflux in Gram-negative bacteria: what are the latest opportunities for drug discovery?
Published in Expert Opinion on Drug Discovery, 2023
Teresa Gil-Gil, Pablo Laborda, Luz Edith Ochoa-Sánchez, José Luis Martínez, Sara Hernando-Amado
Asides from being involved in AR, several efflux pumps have also an important role in the interactions of bacteria with their host, a feature analyzed in detail in the case of bacterial plant pathogens’ efflux pumps, capable of extruding plant-produced anti-virulence compounds [18,19], and of enterobacterial pathogens as Salmonella that requires the activity of the AcrAB efflux pump for resisting the antibacterial effect of bile salts in the intestinal tract [20,21]. It is worth mentioning that, while the activity of some efflux pumps is strictly required for the proficient infection by some pathogens, the opposite can also happen. Indeed, it has been shown that increased expression of some efflux pumps reduces bacterial virulence. This situation has been studied in some detail for Pseudomonas aeruginosa since its efflux pumps can extrude QS signals or their precursors, hence inhibiting the QS response and, consequently impairing the expression of QS-regulated virulence factors [22–30].
Liposomes as vehicles for topical ophthalmic drug delivery and ocular surface protection
Published in Expert Opinion on Drug Delivery, 2021
José Javier López-Cano, Miriam Ana González-Cela-Casamayor, Vanessa Andrés-Guerrero, Rocío Herrero-Vanrell, Irene Teresa Molina-Martínez
Apart from passive diffusion, the presence of efflux and influx membrane transporters in the corneal and conjunctiva cells also plays an important role in drug delivery. The efflux transporters are responsible for decreasing bioavailability expelling the molecules out of the cells. Examples of efflux transporters are P-glycoprotein (P-gp), Breast Cancer Resistance Protein (BCRP) and Multidrug resistance protein (MRP). P-gp is a transporter of lipophilic molecules, which reduce the absorption of lipophilic drugs. Otherwise, MRP transporter effluxes organic anions and conjugated substances and BCRP transporter is also related to drug resistance [66,68]. On the other hand, the role of influx transporters is related to the transport through the membrane of nutrients and xenobiotics, so they are capable of transporting drugs with targeted modifications [70]. There are many types of influx transporters identified in ocular tissues, such as vitamins, glucose, nucleoside and monocarboxylate transporters. Among those, peptide and amino acid transporters are widely applied in ocular drug delivery. Transporter knowledge enables the development of targeted prodrugs capable of being recognized by carriers as substrates increasing ocular absorption [70,80–82].
Novel drug targets for treatment of cryptosporidiosis
Published in Expert Opinion on Therapeutic Targets, 2020
Beilin Wang, Alejandro Castellanos-Gonzalez, A. Clinton White Jr
Despite this plethora of potential targets and high-throughput screening, no compound has succeeded in clinical trials since nitazoxanide. Thus, there is no validated pathway for Cryptosporidium drug development. Unanticipated barriers have arisen that may be unique to this parasite. Its location within vacuoles within the intestinal epithelial cells of the intestine but separated from the host cytoplasm, creates unique challenges for drug pharmacokinetics. Efflux pumps further complicate the pharmacology. Cryptosporidium lacks prokaryote-derived organelles, such as mitochondria and the apicoplast, that have been successfully targeted in malaria and coccidian parasites. Lacking these prokaryotic organelles, the remaining targets are more related to host molecules. Not surprisingly, host toxicities have proven problematic. Unfortunately, toxicities have not been easy to predict. With all of these unanticipated hurdles, wisdom dictates maintaining a diverse pipeline of potential agents.