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Alcohol-Induced Hepatotoxicity
Published in Robert G. Meeks, Steadman D. Harrison, Richard J. Bull, Hepatotoxicology, 2020
An alternate and/or complementary hypothesis to explain the selective perivenular hepatotoxicity of ethanol postulates that the low oxygen tensions normally prevailing in perivenular zones could exaggerate the redox shift produced by ethanol (Jauhonen and co-workers, 1982). This was illustrated in vivo and in the isolated perfused liver, with varying the oxygen supply to reproduce the oxygen tensions prevailing in vivo along the sinusoid (Jauhonen and co-workers, 1985). Varying the oxygen tensions within the physiological range produced a redox gradient of both cytochrome oxidase and NAD+ with a more reduced state at tensions normally prevailing in perivenular zones. The degree of reduction of cytochrome oxidase at these physiological oxygen tensions was not associated with impairment in the ability of the liver to consume oxygen and to produce ATP, suggesting a lack of cellular anoxia. Hepatic oxygen consumption was increased with 25 mM ethanol, but it had no direct effect on the state of reduction of cytochrome oxidase. The effects of ethanol and oxygen tensions on NADH fluorescence were additive, indicating that a greater redox shift should occur when ethanol is oxidized at oxygen tensions similar to those normally prevailing in perivenular zones than at those in periportal zones. This dependence of the ethanol-induced redox shift on oxygen tensions may contribute to the selective perivenular hepatotoxicity of alcohol (Jauhonen and co-workers, 1982).
Intrinsic Optical Properties of Brain Slices: Useful Indices of Electrophysiology and Metabolism
Published in Avital Schurr, Benjamin M. Rigor, BRAIN SLICES in BASIC and CLINICAL RESEARCH, 2020
Thomas J. Sick, Joseph C. LaManna
An important consideration for studies of mitochondrial function is the respiratory chain redox gradient. It is the difference in redox potential between respiratory chain components that provides free energy for synthesis of ATP. We have attempted to quantify cytochrome redox activity in hippocampal slices by expressing light absorption for each cytochrome as a fraction of the total labile signal, i.e., the difference in light absorption obtained in maximally oxidized and maximally reduced states. In practice, the total labile signal is determined at the end of each experiment by first maximally reducing the respiratory chain with nitrogen and then maximally oxidizing the chain components with oxygen and hydrogen peroxide. Difference spectra showing the absorption peaks for cytochrome c (550 nm), cytochrome b (565 nm), and cytochrome a,a3 (605 nm) that illustrate the redox quantitation procedure are presented in Figure 5 (top). The top left difference spectrum shows the total labile signal obtained by comparing peroxide treatment with anoxia. The lower left difference spectrum depicts the absorption changes that occur when comparing normoxia (O2) to anoxia (N2). The spectrum in the right panel shows the difference between normoxia and peroxide, which indicates that cytochrome c (550 nm) and cytochrome b (565 nm) are not fully oxidized under control conditions in the brain slice preparation. Quantitation of redox levels is provided in Figure 5 (bottom), which shows the mitochondrial redox gradient from a hippocampal slice. As expected from studies on isolated mitochondria,35 there is a redox gradient that shows cytochrome b more reduced than cytochrome c, which was more reduced than cytochrome a,a3. This figure also shows the disappearance of the redox gradient during anoxia when all components were fully reduced, a diminution of the gradient following postanoxic reoxygenation due to hyperoxidation of cytochrome b and, to a lesser extent, hyperoxidation of cytochrome c. We have subsequently determined that mitochondrial hyperoxidation is associated with persistent loss of electrical activity in hippocampal slices and is a predictor of functional recovery following global forebrain ischemia in vivo.6
Surface-modified polymeric nanoparticles for drug delivery to cancer cells
Published in Expert Opinion on Drug Delivery, 2021
Arsalan Ahmed, Shumaila Sarwar, Yong Hu, Muhammad Usman Munir, Muhammad Farrukh Nisar, Fakhera Ikram, Anila Asif, Saeed Ur Rahman, Aqif Anwar Chaudhry, Ihtasham Ur Rehman
In the last few decades, surface-modified polymeric nanoparticles have been developed based on only one valuable characteristic, e.g., long circulation, targetability, or stimuli responsiveness. Studies have demonstrated that employing only one strategy in surface-modified nanoparticles is insufficient to transport drugs to tumor tissue effectively. Recently, much research is focused on combining different characteristics of nanoparticles and formulates multifunctional nanoparticles [113]. As an example, stealth nanoparticles are excellent in extended circulation in the bloodstream and passive accumulation inside tumors. However, hydrophilic polymer chains on the surfaces of nanoparticles hinder the interaction of nanoparticles with cancer cells. Development of multifunctional nanoparticles, such as conjugation of targeting ligands on the surfaces of stealth nanoparticles, can decrease these problems and improve the interaction of nanoparticles with cancer cells [114]. Similarly, stimuli-sensitive property, such as reduction-induced degradation, can be introduced in multifunctional nanoparticles along with targetability and longevity. For instance, our group formulated nanoparticles composed of PCL-SS-PEG and PCL-PEI-Fol copolymers. These nanoparticles contain three characteristics, i.e. they could circulate safely during blood circulation, accumulate in tumor tissue passively, and shed the outer layer to target cancer cells [94]. Since pH and redox gradient usually coexist in tumor tissues, acid and reduction sensitivity can be brought in nanoparticles collectively. Surface modification with acid sensitive and reducible linkages produces better results in drug delivery of anticancer drugs [115]. Thermally sensitive NGR peptide targeted nanoparticles are also synthesized, which overexpress in tumor vasculature and release the drug in tumor at 41°C whereas minimal release at 37°C [116]. The surfaces of magnetic nanoparticles are widely modified with hydrophilic polymers and targeting agents, e.g. anti-VEGF monoclonal antibody was conjugated on the surface of magnetic nanoparticles for radioimmunotherapy of liver cells under the influence of magnetic field [117]. Overall, the combination of more than one strategy in surface-modified polymeric nanoparticles provides a flourishing area for the anticancer drug transportation system.